Compositions comprising HDAC-11 inhibitors and methods of use thereof

Abstract

Disclosed herein are compounds and pharmaceutical formulations that can suppress and / or inhibit activity levels of HDAC11. Also disclosed are methods of using these compounds and pharmaceutical formulations to treat cancer, to slowing disease progression, to reduce tumor growth and migration, to treat multiple sclerosis, and to treat a neurological disease or disorder.

Description

GW173 (091019-869493)COMPOSITIONS COMPRISING HDAC-11 INHIBITORSAND METHODS OF USE THEREOFI. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 761,512 filed 21 February 2025, which is incorporated herein by reference in its entirety.II. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support under R01 Al 153110, R01 AI153110 / 01A1, and R01 CA240529 awarded by the National Institutes of Health. The government has certain rights in the invention.III. REFERENCE TO THE SEQUENCE LISTING

[0003] The Sequence Listing submitted 20 February' 2026 as an XML file namedc“GW173_091019-869493_SL”, created on 12 February’ 2026 and having a size of 204,800 bytes is hereby incorporated by reference pursuant to 37 C.F.R. § 1.52(e)(5).IV. BACKGROUND

[0004] For decades, the foundations of cancer treatment have been surgery7, chemotherapy, and radiation therapy. These continue to be critical mainstays of treatment, but new- categories of treatment have recently helped transform the treatment picture for people with cancer. For example, it is highly desirable to exploit cancer-specific markers for therapeutic development.

[0005] Thus, there remains a need for effective and non-invasive methods of treating cancer, slowing disease progression, and / or reducing tumor growth and migration. The compositions and methods disclosed herein meet this need.V. BRIEF DESCRIPTION OF THE FIGURES

[0006] FIG.1A- FIG. IE show- the development and characterization of new- HD AC 11 inhibitors and their specificity in cell-based assays. FIG. 1A shows chemical structures and ICN values of Trapoxin A and TD034-(S) against HDAC11. FIG. IB shows the structure-activity summary of newly developed cyclic peptide HDAC11 inhibitors. FIG. 1C shows the cellular engagement of HDAC11 by TD047-click in HEK293T cells. Cells were treated with indicated concentrations of TD047-click for 1 h, followed by biotin-azide conjugation via click chemistry and streptavidin pulldown. HD AC 11 was detected by immunoblotting. FIG. ID shows the SHMT2 acylation levels in HEK293T cells treated with TD034, TD047, or TD048 at indicated concentrations. FIG. IE shows that TD047 and TD048 do not inhibit HDAC1, HDAC6, SIRT1, or SIRT2 in cells. Acetylation of p53, a-tubulin, and histone H3 was used as readouts. GAPDH served as loading control.GW173 (091019-869493)

[0007] FIG. 2A - FIG. 2H show that HD AC 11 inhibitors suppressed tumor growth across multiple cancer types with enhanced sensitivity in melanoma. FIG. 2A shows dose-response curves of B16-F10, A2058, and G361 cells treated with SIS 17, TD034, TD047, or TD048 for 72 hours. FIG. 2B shows representative images of colony formation assays in B16-F10 and A2058 cells treated with the indicated inhibitors at various concentrations. FIG. 2C shows cell viability- assessed by luminescence in B16-F10, A2058, and G361 cells transfected with control (siNC) or HDAC11-targeting siRNA (siHDACl 1) for 72 hours. FIG. 2D shows representative images of tumors from B16-F10 xenografts in mice treated with vehicle or TD047 (20 mg / kg daily for 9 days). FIG. 2E shows tumor growth curves showing significantly reduced tumor volume in TD047-treated mice (n = 4 per group). FIG. 2F shows final tumor weights are significantly reduced in the TD047 group compared to vehicle. FIG.2G shows body weight monitoring during treatment indicates minimal systemic toxicity. FIG. 2H shows a western blot analysis of YAP in tumor lysates shows decreased YAP protein levels upon TD047 treatment.

[0008] FIG. 3A - FIG. 3M shows that HDAC11 inhibition destabilized YAP via enhanced ubiquitination and suppresses cancer cell migration. FIG. 3A - FIG. 3B shows Western blot analyses showing decreased YAP protein levels in B16-F10 and A2058 cells upon HDAC11 knockdown (FIG. 3A) or treatment with HDAC11 inhibitors (FIG. 3B), with actin as a loading control. FIG. 3C shows transwell migration assays of B16-F10 and A2058 cells transfected with siNC, siHDAC 11 , or siYAP and treated with DMSO or 2 pM TD047 for 24 hours. Representative images (top panel) and quantification (bottom panel) show' that HD AC 11 inhibition or YAP depletion significantly suppresses migration. Data are mean ± SD from three independent experiments. ***is p < 0.001. FIG.3D - FIG.3F show the qRT-PCR analysis of canonical YAP target genes (CTGF and CYR61) and YAP mRNA levels. FIG. 3D shows B16-F10 cells treated with TD047 (1 pM or 2 pM). FIG. 3E shows A2058 cells stably expressing control or two independent shRNAs targeting HDAC11. FIG. 3F show's B16-F10 cells transfected with control or two independent siRNAs targeting HDAC11. In all conditions, CTGF and CYR61 expression is significantly reduced, whereas YAP mRNA levels remain largely unchanged, indicating that HDAC11 regulates YAP primarily through a post-transcriptional mechanism. Data are presented as mean ± SD from three independent biological replicates. Statistical significance was determined by tw'O-tailed Student’s t-test. p < 0.05; NS, not significant. FIG.3G - FIG.3J shows the ubiquitination assays in HEK293T cells co-transfected with FLAG-YAP and HA-ubiquitin. TD047 treatment (FIG. 3G), HD AC 11 knockdown (FIG. 3H, FIG. 31), or siRNA (FIG. 3 J) enhances YAP ubiquitination, as detected by immunoprecipitation (IP) of FLAG-YAP and immunoblotting for HA. FIG.3K show s that the overexpression of GFP-HDAC 11 reduced YAPGW173 (091019-869493)ubiquitination. while the catalytically inactive Y304H mutant failed to do so, indicating that HD AC H’s de-fatty acylase activity stabilized YAP. FIG. 3L shows a cycloheximide (CHX) chase assay showing accelerated YAP degradation in B16-F10 cells treated with TD047 (2 pM), confirming reduced YAP stability' upon HDAC11 inhibition. FIG. 3M shows a Western blot analysis of YAP protein levels in B16-F10 cells treated with TD047 (1 pM or 2 pM) in the presence or absence of the proteasome inhibitor MG132. MG132 restores YAP levels, indicating that HDAC11 inhibition promotes proteasome-dependent degradation of YAP.

[0009] FIG. 4A - FIG. 41 shows that HD AC 11 regulated YAP de-fatty acylation. FIG. 4A shows that YAP is fatty acylated in cells. HEK293T cells were transfected with FLAG-YAP and metabolically labeled with Alkl4, followed by click chemistry and detection with streptavidin-HRP after FLAG immunoprecipitation. FIG.4B and FIG.4C show the knockdown of HD AC 11 by shRNA (FIG. 4B) or siRNA (FIG.4C) increases YAP fatty acylation in HEK293T cells. YAP fatty acylation was assessed after Alkl4 labeling and FLAG-IP. Right: qRT-PCR confirms HDAC11 knockdown efficiency. FIG.4D and FIG. 4E shows the pharmacological inhibition of HD AC 11 using TD034 (FIG. 4D) or TD047 (FIG. 4E) elevates YAP fatty acylation in a dosedependent manner. FLAG-YAP expressing cells were treated with inhibitors, labeled with Aik 14, and analyzed via click chemistry and streptavidin-HRP blotting. FIG.4F and FIG. 4G shoyv the overexpression of WT HDAC11, but not the catalytic mutant Y304H, reduced YAP fatty' acylation. Cells co-expressing FLAG-YAP and GFP-HDAC11 (WT or Y304H) were subjected to Alkl4 labeling and fatty acylation detection as described. FIG. 4H shows coimmunoprecipitation reveals that HD AC 11 physically interacts with YAP. FLAG-YAP and GFP-HDAC11 co-expression folloyved by FLAG-IP and GFP immunoblot confirmed the interaction.FIG. 41 shows GST pulldoyvn assay demonstrates a direct physical interaction between purified HD AC 11 and YAP proteins. Recombinant GST-YAP immobilized on glutathione beads was incubated with purified His-tagged HDAC11, followed by immunoblotting for His-HDACl 1.

[0010] FIG. 5A - FIG. 51 shows fatty' acylation at K181 and K254 separately regulated YAP nuclear localization and ubiquitination. FIG. 5A show s fatty acylation of FLAG-YAP WT and lysine-to-arginine (K— >R) mutants in HEK293T cells treated with Alkl4 (50 pM, 6 hours). Click chemistry and streptavidin-HRP detection after FLAG immunoprecipitation revealed reduced acylation in K181R and K254R mutants. FIG. 5B show's qPCR analysis of YAP target genes (CCL2, CTGF, CYR61) in YAP knockout cells reconstituted with WT, K181R, orK254R. K181R reconstitution led to enhanced target gene expression. Data are presented as mean ± SD, * means p < 0.05. FIG.5C shows the immunofluorescence images showing the subcellular localization of FLAG-YAP WT and KR mutants in HEK293T cells after Alkl4 labeling (50 pM, 24 hours).GW173 (091019-869493)K181R predominantly localizes in the nucleus, while WT and K254R remain cytoplasmic. FIG.5D - FIG. 5E shows quantification of nuclear versus cytoplasmic YAP localization in YAP-KO cells reconstituted with K254R (FIG. 5D) or K181R (FIG. 5E) mutants. Confocal imaging confirmed distinct localization patterns driven by site-specific fatty' acylation. FIG. 5F shows ubiquitination assays comparing FLAG-YAP K181R and K254R mutants co-expressed with His-tagged ubiquitin (His-ub) under combined Alkl4 labeling and HDAC11 inhibition (TD047, 2 pM). Under these conditions, robust inducible ubiquitination was observed in KI 81R-expressing cells, whereas ubiquitination was markedly reduced in K254R-expressing cells, indicating that fatty acylation at K254 is specifically required for inducible YAP ubiquitination. FIG.5G shows control ubiquitination assay performed in the absence of Alkl4 labeling. WT. K181R, and K254R YAP exhibited comparable basal ubiquitination, indicating that K254 is not a dominant ubiquitin acceptor site. FIG. 5H - FIG. 51 shows a systematic analysis of YAP ubiquitination across multiple KR mutants following Alkl4 labeling (50 pM, 24 hours). Among all mutants examined, only K254R substantially reduced Alkl4-induced ubiquitination, whereas mutations at other lysine residues had minimal effects.

[0011] FIG. 6A - FIG. 61 show that HDAC11 inhibition disrupts YAP-TEAD binding and enhances nuclear retention via CRM1 interaction Modulation. FIG.6A - FIG. 6B show the coimmunoprecipitation (co-IP) of FLAG-YAP following Alkl4 labeling (50 pM. 24 hr) and HD AC 11 knockdown (FIG.6A) or TD047 treatment (FIG.6B). Both genetic and pharmacologic inhibition of HD AC 11 reduced YAP-TEAD binding, while YAP interaction with 14-3-3 and phosphorylation at Serl27 (pYAPAS127) remained unchanged. FIG. 6C - FIG. 6E provide an immunofluorescence analysis showing subcellular localization of endogenous YAP. Knockdown of HD AC 11 (FIG. 6C) or TD047 treatment (2 pM, 24 hours) (FIG. 6E) increased nuclear retention of YAP, whereas HDAC11 overexpression (FIG. 6D) promoted cytoplasmic sequestration. FIG. 6F provides immunofluorescence staining showing that TD034 (10 pM, 24 hours) increased nuclear retention of YAP but had minimal effect on TAZ localization, indicating specificity' in HDAC11-YAP regulation. FIG. 6G and FIG. 6H show the co-IP of FLAG-YAP demonstrating that HDAC11 knockdown (FIG. 6G) or TD047 treatment (FIG. 6H) enhanced YAP-CRM1 binding, consistent with nuclear retention. TEAD binding was concurrently reduced. FIG. 61 shows the co-IP analysis of FLAG-tagged YAP mutants after Alkl4 treatment revealed that the K181R mutant exhibited diminished CRM1 binding and increased TEAD association, indicating that fatty acylation at KI 81 modulates YAP's nucleo-cytoplasmic shuttling and transcriptional engagement.GW173 (091019-869493)

[0012] FIG. 7A - FIG. 7K show that HDAC11 expression is elevated in multiple cancer types and its knockdown suppresses tumor growth in xenograft animal models. FIG. 7A - FIG. 7C show boxplot analysis of HD AC 11 gene expression from the TNMplot database comparing normal and tumor tissues in lung cancer (FIG. 7A), breast cancer (FIG. 7B), and liver cancer (FIG. 7C). HD AC 11 is significantly upregulated in all three tumor types compared to corresponding normal tissues (p < 0.001). FIG. 7D, FIG. 7E, and FIG. 7H show a heatmap visualization of HDAC1 1 expression from three independent GEO datasets: lung cancer (GSE 19804) (FIG. 7D), liver cancer (GSE76427) (FIG. 7E), and breast cancer (GSE10810) (FIG. 7H). In each dataset, HD AC 11 expression is consistently elevated in tumor samples compared to paired or matched normal samples. FIG. 7F, FIG. 7G, and FIG. 71 are boxplots showing quantitative HDAC11 probe expression values from the same GEO datasets: GSE19804 (FIG. 7F), GSE76427 (FIG. 7G), and GSE 10810 (FIG. 71). Statistically significant increases in HDAC11 expression are observed in tumor tissues across all three cancer types (p < 0.001). FIG.7 J and FIG.7K show knockdown of HD AC 11 suppresses tumor growth in vivo. A549 (FIG. 7 J) and H1299 (FIG. 7K) lung cancer cells stably expressing two independent HDAC11 shRNAs (shl, sh2) or wild-type control (WT) were subcutaneously injected into nude mice. Representative images of tumors and corresponding quantification of tumor weight show that HD AC 11 knockdown significantly reduces tumor growth (mean ± SEM, n = 6-8 tumors per group, p < 0.01).

[0013] FIG.8A - FIG.8H show the synthesis of new HDAC11 inhibitors (related to FIG. 1A -FIG. IE). FIG.8A shows a western blot analysis of HD AC 11 expression across a panel of human cancer cell lines, including NSCLC (H2122, H1299, H23, H1975, H522, A549), melanoma (A375), and non-tumorigenic (BEAS2B, 293T) lines. HDAC11 levels varied among cell types. ACTIN serves as a loading control. FIG. 8B - FIG. 8D are cell proliferation assays in NSCLC cell lines A549 (FIG. 8B), H1299 (FIG. 8C), and H23 (FIG. 8D) treated with DMSO or increasing concentrations of TD034 (5 pM, 10 pM). TD034 treatment significantly reduced cell growth in a dose-dependent manner over a 6-day period. FIG. 8E - FIG. 8G show colony¬ formation assays in A549 (FIG. 8E). Hl 299 (FIG. 8F), and H23 (FIG. 8G) cells treated with DMSO or TD034 (5 pM, 10 pM). TD034 effectively suppressed long-term clonogenic survival in all three lines, as visualized by crystal violet staining. FIG. 8H shows an in vivo efficacy study of TD034 in an H1299 NSCLC xenograft model. Tumor-bearing nude mice w ere treated with vehicle, TD034 (20 mg / kg). or TD034 (80 mg / kg). No significant tumor growth inhibition was observed in either treatment group, highlighting the need for more potent and stable HD AC 11 inhibitors for in vivo efficacy.GW173 (091019-869493)

[0014] FIG.9A - FIG.9D show the Synthesis of new HDAC11 inhibitors (related to FIG. 1A -FIG. IE). Synthesis of new HD AC 11 inhibitors: hydroxyketone warheads (FIG. 9 A); Amino acid (FIG.9B); amino acid 12 (FIG. 9C); and cyclic peptide inhibitors (FIG. 9D).

[0015] FIG. 10A - FIG. 10E show that HD AC 11 knockdown inhibited proliferation and colony formation in melanoma cells (related to FIG. 2A - FIG. 2H). FIG. 10A - FIG. 10C show cell proliferation assays of melanoma cell lines A2058 (FIG. 10A), G361 (FIG. 10B), and B16-F10 (FIG. 10C) stably expressing control (shCON) or HDAC11 -targeting shRNAs (shHDACl l-1, shHDAC 11 -2). Knockdown of HD AC 11 significantly reduced cell growth over time as measured by OD at 490 nm. Quantitative RT-PCR (bottom panels) confirmed efficient knockdown of HDAC11 expression. Data represent mean ± SD of three biological replicates; * means p < 0.05.FIG. 10D shows colony formation assay and Western blot validation in B16-F10 cells expressing shHDAC 11 versus shNC. HD AC 11 knockdown markedly reduced colony formation. Western blot confirmed reduced HD AC 11 protein expression.

[0016] FIG. 10E shows representative colony formation assays in A2058 and G361 melanoma cells with stable HDAC11 knockdown. Depletion of HD AC 11 significantly impaired long-term clonogenic potential, consistent with its role in supporting tumor cell growth.

[0017] FIG. 11A - FIG. 11H shows that HDAC11 inhibition reduced YAP stability and activity7independent of the Canonical Hippo Pathway (related to FIG. 3A - FIG.3M). FIG. 11A - FIG.11B show cell proliferation assays (CCK-8) in A2058 (FIG. 11 A) and G361 (FIG. 11B) melanoma cells transfected with control siRNA (DMSO), TD047 (2 pM), siYAP, or siYAP combined with TD047. Knockdown of YAP or treatment with TD047 each partially reduced proliferation and their combination resulted in additive inhibition. Data represent mean ± SD (n = 3); p < 0.01, NS = not significant. FIG. 11C shows western blot analysis of Hippo pathway proteins in A2058 cells treated with DMSO, HD AC 11 inhibitor (5 pM and 10 pM). Inhibitor treatment decreased YAP and its downstream transcriptional targets (CTGF, CYR61) without affecting phosphorylation of upstream kinases (MST1, p-MSTl, LATS1, p-LATSl). Quantitative PCR (right panel) shows that HD AC 11 inhibition significantly suppressed YAP target gene expression without altering YAP mRNA levels. Data represent mean ± SD (n = 3); * means p < 0.05. IG. 11D shows dose-dependent overexpression of GFP-HDAC11 (1 pg - 8 pg) in A2058 cells increased total YAP protein levels. qPCR analysis (right) showed corresponding increases in CTGF and CYR61 expression. These effects were dose-dependent and saturated at 8 pg. YAP mRNA levels were unchanged. FIG. HE shows that HD AC 11 knockdown in H1299 cells reduced YAP protein levels (left) and significantly decreased CTGF and CYR61 expression, as shown by qPCR (bottom right). YAP mRNA w ere unaffected. Quantification of YAP proteinGW173 (091019-869493)levels (top right) confirmed the decrease. * means p < 0.05 compared to control. FIG. 11F - FIG.11H shows western blot and qPCR analyses in H1299 (FIG. 11F), A549 (FIG. 11G), and H522 (FIG. 11H) lung cancer cells treated with DMSO or an HD AC 11 inhibitor (5 pM and 10 pM). HDAC11 inhibition reduced YAP protein abundance in all three lines without altering upstream Hippo pathway components (p-YAP127, MST1. LATS1). qPCR confirmed downregulation of CTGF and CYR61, with YAP mRNA levels unchanged.

[0018] FIG. 12A - FIG. 12M show ALK14-induced fatty acylation promoted YAP degradation across multiple cancer cell lines (related to FIG.4A - FIG.41). FIG. 12A - FIG. 12F shows the quantitative PCR analysis ofYAP target gene expression (CTGF, CYR61) and YAP mRNA levels in melanoma (A2058, G361, B16-F10; FIG. 12A - FIG. 12C) and lung cancer (A549, H1299, H522; FIG. 12D - FIG. 12F) cell lines following treatment with DMSO or ALK14 (50 pM, 24 h). ALK14 significantly reduced CTGF and CYR61 expression across all lines, while YAP mRNA levels remained largely unchanged, indicating a post-transcriptional regulatory mechanism. Data are presented as mean ± SD (n = 3). * means p < 0.05, ** means p < 0.01 (unpaired two-tailed t test); NS means not significant. FIG. 12G - FIG. 12K shows western blot analysis of YAP protein levels in the same cell lines treated with DMSO or ALK14 (50 pM, 24 hours). ALK14 treatment led to a marked decrease in YAP protein levels across both melanoma (FIG. 12G -FIG. 121) and lung cancer models (FIG. 12J - FIG. 12K), consistent with fatty acylationdependent YAP destabilization. GAPDH was used as loading control. FIG. 12L shows the fatty acylation screen of YAP lysine mutants. HEK293T cells were transfected with FLAG-tagged YAP constructs carrying lysine-to-arginine substitutions, followed by Alkl4 labeling (50 pM, 6 hours) and click chemistry. Mutations at KI 81 and K254 abolished fatty acylation, while other mutants (e g., K76R, K90R. K280R) showed no change, confirming these two residues as major sites of YAP fatty acylation. FIG. 12M is a sequence alignment ofYAP proteins from multiple species (human, mouse, zebrafish, chicken, etc.) demonstrates that KI 81 and K254 are evolutionarily conserved. underscoring their potential regulatory significance.

[0019] FIG. 13A - FIG. 13G show the functional validation ofYAP fatty acylation sites KI 81 and K254 (related to FIG.5A - FIG.5L). FIG. 13A - FIG. 13B show quantitative PCR analysis ofYAP target genes (CTGF and CYR61) in A2058 (FIG. 13A) and G361 (FIG. 13B) melanoma cells. YAP-knockout (KO) cells were reconstituted with wild-type (WT) or double-mutant (K181R / K254R, 2KR) YAP and treated with or without ALK14 (50 pM, 24 hours). ALK14 significantly suppressed YAP target gene expression in WT- but not 2KR-expressing cells, indicating the importance of KI 81 and K254 for ALK14-induced transcriptional repression. Data are representative of three independent experiments with similar results; * means p < 0.05; NSGW173 (091019-869493)mean not significant (unpaired two-tailed t-test). FIG. 13C - FIG. 13D show cell proliferation curves of A2058 (FIG. 13C) and G361 (FIG. 13D) cells under the indicated genetic and treatment conditions. ALK14 treatment significantly reduced the growth of WT-expressing cells but had minimal effect on 2KR-expressing cells. Data are representative of three independent experiments. FIG. 13E - FIG. 13F are representative images of colony formation assays in A2058 (FIG. 13E) and G361 (FIG. 13F) cells without ALK14 treatment. YAP-knockout (KO) reduced colony formation, which was restored upon reconstitution with WT YAP. Notably, the K181R / K254R double mutant (2KR) also restored clonogenic capacity, and in some cases exceeded that ofWT, indicating that loss of fatty acylation may enhance YAP’s transcriptional or proliferative activity. Representative of three independent experiments. FIG. 13G is a schematic domain map of the human YAP protein, highlighting the positions of KI 81 (within the WW1 domain) and K254 (within the WW2 domain) as key fatty acylation sites. These residues are functionally implicated in regulating YAP subcellular localization and stability.

[0020] FIG. 14A - FIG. 14B show bioinformatic validation of HDAC11 and YAP expression across multiple cancer datasets (related to FIG. 7A - FIG. 7K). FIG. 14A shows Kaplan-Meier survival curves showing that high HD AC 11 expression correlates with significantly reduced overall survival in breast (GSE10810) and liver cancer (GSE76427), but not in lung cancer (GSE19804), using different probes. FIG. 14B shows boxplots showingYAPl mRNA expression across normal and tumor tissues in lung (GSE19804). breast (GSE10810). and liver cancer (GSE76427). YAP expression was not consistently elevated, indicating post-transcriptional regulation by HD AC 11.

[0021] FIG. 15 is a schematic model of HD AC 11 -mediated regulation of YAP fatty acylation and its impact on YAP localization and stability. FIG. 15 shows schematic representation of HDAC 11 -regulated YAP de-fatty acylation. Long-chain fatty acids (FAs) were metabolized intracellularly and used for protein fatty acylation. In this model, YAP underwent lysine fatty acylation at KI 81 and K254. Fatty acylation at KI 81 promoted CRMl / exportin-1 -mediated nuclear export of YAP, whereas K254 acylation stabilized YAP by preventing its ubiquitination and proteasomal degradation. HDAC 11 functioned as a de-fatty acylase that removed these modifications, retaining YAP in the cytoplasm and reducing its transcriptional activity. This regulatory mechanism impacted YAP-TEAD interactions and dow nstream gene expression.

[0022] FIG. 16 shows HDAC 11 expression in several types of cancer cells compared to both metastatic levels and control / normal levels.

[0023] FIG. 17 shows HDAC 11 expression across various human brain tissues and cell types. HDAC 11 shows notably high expression in oligodendrocytes and oligodendrocyte precursor cellsGW173 (091019-869493)(highlighted with the oval annotation). Expression was more moderate to low across most other brain regions. The oligodendrocyte lineage cells clearly stood out as the primary sites of HDAC11 expression in this dataset, indicating the involvement of HD AC 11 in CNS functions in addition cancer.

[0024] FIG. 18 shows Western blot analysis of HDAC11 and NCDN expression across various human tissues. HDAC11 showed predominantly brain-enriched expression with an intense band in the brain lane (marked with the arrow). Much weaker expression was detected in other organs. NCDN (neurochondrin, a neuron-specific HDAC11 -interacting protein) showed a similar brain-predominant pattern, with strong expression in brain and weaker bands in other organs. The data confirmed that HD AC 11 protein was highly enriched in brain tissue compared to other organs examined.

[0025] FIG. 19A shows an AlphaFold prediction of the protein-protein interaction between NCDN (neurochondrin) and HDAC11. Left panel is a 3D structural model showing the predicted NCDN-HDAC11 complex, with the two proteins displayed in ribbon representation with distinct shading. Right panel is a contact map / predicted aligned error (PAE) matrix displaying the confidence of residue-residue interactions between the two proteins. Regarding the interaction confidence, the prediction had a pTM score of 0.58, which indicates moderate confidence in the predicted interface. The pTM (predicted template modeling) score ranges from 0 to 1, with higher values indicating greater confidence. This computational prediction indicated that NCDN and HD AC 11 could physically interact, consistent with their co-expression in brain tissue. FIG. 19B and FIG. 19C show physical interaction between NCDN and HDAC11 through coimmunoprecipitation experiments using tagged proteins expressed in HEK293T cells (FIG. 19B) and endogenous (native) proteins from brain mixed culture cells, with pharmacological treatments (FIG. 19C). These results confirmed that NCDN and HDAC11 physically interacted both when overexpressed and when at endogenous levels in brain-derived cells.

[0026] FIG. 20A - FIG. 20C show that NCDN underwent lysine fatty acylation, which was enhanced by HDAC11 inhibition. The results demonstrate that NCDN was a substrate for lysine fatty acylation, and HD AC 11 appeared to function as a defatty -acyl as e that removed this modification from NCDN.

[0027] FIG. 21A and FIG. 21B identified K272 (lysine 272) as a specific fatty acylation site on NCDN through lysine-to-arginine mutagenesis. These data demonstrate that K272 was the key lysine fatty acylation site on NCDN that was regulated by HDAC11 defatty-acylase activity

[0028] FIG. 22A - FIG. 22C show that HD AC I l's catalytic activity was needed to regulate NCDN fatty acylation through overexpression studies in HEK293T cells. Wild-type HD AC 11,GW173 (091019-869493)but not its catalytically inactive mutant (Y304H), reduced NCDN fatty acylation. These data demonstrate that HDAC1 l's enzymatic defatty-acylase activity was necessary for removing fatty acyl groups from NCDN at K272.

[0029] FIG. 23A - FIG. 23C show genetic knockdown or pharmacological inhibition of HD AC 11 increased NCDN fatty acylation levels, providing complementary loss-of-function evidence. These results conclusively showed that both genetic (HD AC 11 knockdown) and pharmacological (TD047 or ALK14 inhibitors) approaches to reduce HDAC11 activity resulted in increased NCDN fatty acylation, confirming HDAC11 functioned as a defatty-acylase that removes fatty acyl modifications from NCDN in cells.

[0030] FIG.24A - FIG. 24B shows that HDAC11 inhibitors increased endogenous NCDN fatty acylation in primary brain mixed culture cells, demonstrating physiological relevance. HDAC11 regulated NCDN fatty acylation at endogenous protein levels in brain-derived cells, supporting the physiological relevance of this regulatory mechanism in the nervous system.

[0031] FIG. 25A - FIG. 25B shows that NCDN physically interacted with mGluR5 (metabotropic glutamate receptor 5), and that HD AC 11 inhibition strengthened this interaction, with proteomic analysis revealing affected biological pathways. The overall conclusion were: (i) NCDN directly interacted with mGluR5, a key glutamate receptor; (ii) HD AC 11 inhibition increased NCDN fatty acylation, which enhanced NCDN-mGluR5 binding; (iii) this regulator ' mechanism affected multiple cellular pathways, particularly GPCR signaling, signal transduction, and immune responses; and (iv) HDAC11 -mediated regulation of NCDN fatty' acylation had broad functional consequences for neuronal signaling and cellular processes.

[0032] FIG. 26A - FIG. 26C show' the functional consequences of HD AC 11 inhibition on intracellular calcium signaling and MAPK pathway activation in brain cells, connecting NCDN fatty acylation to downstream cellular responses. These data show that HDAC11 inhibition increased NCDN fatty acylation, which enhanced mGluR5 -mediated calcium signaling and MAPK activation, promoting beneficial effects in neurodegenerative conditions like multiple sclerosis through improved oligodendrocy te function and remyelination.

[0033] FIG. 27A - FIG. 27B show that HD AC 11 inhibition promoted NCDN membrane localization through fatty' acylation at K272, using cellular fractionation experiments. This mechanism explains how HD AC 11 regulated NCDN function through controlling its subcellular localization via fatty acylation status.VI. BRIEF SUMMARY

[0034] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof:GW173 (091019-869493)Formula (I), wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3. R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon.

[0035] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof:Formula (I); wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3, R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon; with the proviso that the compound is not (3S,6S.9S,15aR)-6,9-Dibenzyl- 3-(6-oxo-6-((2S.3R)-3-undecyloxiran-2-yl)hexyl)octahydro-2H-pyrido[l, 2-a][l. 4, 7, 1 O]tetraazacyclododecine- 1 ,4,7, 10(3H, 12H)-tetraone or (3S,6S,9S, 127?)-3,6-dibenzyl-9-[6-[(2S')- oxiran-2-yl]-6-oxohexyl]-l ,4,7, 10-tetrazabicyclo[l 0.4.0]hexadecane-2,5,8, 11-tetrone.

[0036] Disclosed herein is TD047. Disclosed herein is TD048.

[0037] Disclosed herein is a pharmaceutical formulation comprising a disclosed compound and one or more pharmaceutically acceptable carriers.

[0038] Disclosed herein is a pharmaceutical formulation comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof:Formula (I), wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can beGW173 (091019-869493)hydrogen or -OR3. R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon; and one or more pharmaceutically acceptable carriers.

[0039] Disclosed herein is a pharmaceutical formulation comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof:Formula (I); wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3, R3 can be hy drogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon: with the proviso that the compound is not (3S,6S.9S,15aR)-6,9-Dibenzyl-3-(6-oxo-6-((2S,3R)-3-undecyloxiran-2-yl)hexyl)octahydro-2H-pyrido[l, 2-a][l, 4, 7, 10]tetraazacyclododecine-l,4,7,10(3H,12H)-tetraone or (3S,6S,95,12J?)-3,6-dibenzyl-9-[6-[(2S)-oxiran-2-yl]-6-oxohexyl]-l,4,7,10-tetrazabicyclo[10.4.0]hexadecane-2,5,8,l 1-tetrone; and one or more pharmaceutically acceptable carriers.

[0040] Disclosed herein is a pharmaceutical formulation comprising one or more disclosed compound and one or more pharmaceutically acceptable carriers.

[0041] Disclosed herein is a pharmaceutical formulation comprising one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof:Formula (I), wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3. R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon: and one or more pharmaceutically acceptable carriers.

[0042] Disclosed herein is a pharmaceutical formulation comprising one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof:GW173 (091019-869493)Formula (I); wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3. R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon: with the proviso that the compound is not (3S,6S.9S,15aR)-6,9-Dibenzyl- 3-(6-oxo-6-((2S,3R)-3-undecyloxiran-2-yl)hexyl)octahydro-2H-pyrido[l, 2-a][l, 4, 7, 10]tetraazacyclododecine-l,4,7,10(3H,12H)-tetraone or (35',6S,91S',127?)-3,6-dibenzyl-9-[6-[(2S)- oxiran-2-yl]-6-oxohexyl]-l,4,7,10-tetrazabicyclo[10.4.0]hexadecane-2,5,8,l 1-tetrone; and one or more pharmaceutically acceptable carriers.

[0043] Disclosed herein is a pharmaceutical formulation comprising TD047 and one or more pharmaceutically acceptable carriers.

[0044] Disclosed herein is a pharmaceutical formulation comprising TD047 and one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof:Formula (I), wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3. R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon; and one or more pharmaceutically acceptable carriers.

[0045] Disclosed herein is a pharmaceutical formulation comprising TD047 and one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof:Formula (I); wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can beGW173 (091019-869493)hydrogen or -OR3. R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon; with the proviso that the compound is not (3S,6S,9S,15aR)-6,9-Dibenzyl- 3-(6-oxo-6-((2S,3R)-3-undecyloxiran-2-yl)hexyl)octahydro-2H-pyrido[l, 2-a][l, 4, 7, 10]tetraazacyclododecine-l,4,7,10(3H,12H)-tetraone or (3S,6S,9S,127?)-3,6-dibenzyl-9-[6-[(2S)- oxiran-2-yl]-6-oxohexyl]-l,4,7,10-tetrazabicyclo[10.4.0]hexadecane-2,5,8.11-tetrone; and one or more pharmaceutically acceptable carriers.

[0046] Disclosed herein is a method of treating cancer, slowing disease progression, and / or reducing tumor grow th and migration, the method comprising administering to the subject in need thereof a therapeutically effective amount of a disclosed compound or a pharmaceutical formulation thereof.

[0047] Disclosed herein is a method of treating cancer, slowing disease progression, and / or reducing tumor grow th and migration, the method comprising administering to the subject in need thereof a therapeutically effective amount of a disclosed compound of Formula (I) or a pharmaceutical formulation thereof.Formula (I), wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3. R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon, or a pharmaceutically acceptable salt thereof.

[0048] Disclosed herein is a method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, the method comprising administering to the subject in need thereof a therapeutically effective amount of a disclosed compound of Formula (I) or a pharmaceutical formulation thereof.Formula (I); wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3, R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotesGW173 (091019-869493)can be a chiral carbon: with the proviso that the compound is not (3S,6S.9S,15aR)-6,9-Dibenzyl- 3-(6-oxo-6-((2S,3R)-3-undecyloxiran-2-yl)hexyl)octahydro-2H-pyrido[l, 2-a][l, 4, 7, 10]tetraazacyclododecine-l,4,7,10(3H,12H)-tetraone or (3S,65 95,127?)-3,6-dibenzyl-9-[6-[(2S)- oxiran-2-yl]-6-oxohexyl]-l,4,7,10-tetrazabicyclo[10.4.0]hexadecane-2,5,8,l 1-tetrone; and one or more pharmaceutically acceptable carriers.

[0049] Disclosed herein is a method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, the method comprising administering to the subject in need thereof a therapeutically effective amount of TD047 or a pharmaceutical formulation thereof. Disclosed herein is a method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, the method comprising administering to the subject in need thereof a therapeutically effective amount of TD047 or a pharmaceutical formulation thereof and administering one or more disclosed HDAC11 inhibitors or a pharmaceutical formulation thereof.

[0050] Disclosed herein is a method of treating multiple sclerosis, the method comprising administering to the subject in need thereof a therapeutically effective amount of a disclosed compound or a pharmaceutical formulation thereof.

[0051] Disclosed herein is a method of treating multiple sclerosis, the method comprising administering to the subject in need thereof a therapeutically effective amount of a disclosed compound of Formula (I) or a pharmaceutical formulation thereof,Formula (I), wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3. R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon, or a pharmaceutically acceptable salt thereof.

[0052] Disclosed herein is a method of treating multiple sclerosis, the method comprising administering to the subject in need thereof a therapeutically effective amount of a disclosed compound of Formula (I) or a pharmaceutical formulation thereof,GW173 (091019-869493)Formula (I); wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3. R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon: with the proviso that the compound is not (3S,6S.9S,15aR)-6,9-Dibenzyl-3-(6-oxo-6-((2S,3R)-3-undecyloxiran-2-yl)hexyl)octahydro-2H-pyrido[l, 2-a][l, 4, 7, 10]tetraazacyclododecine-l,4,7,10(3H,12H)-tetraone or (35',6S,91S',127?)-3,6-dibenzyl-9-[6-[(2S)-oxiran-2-yl]-6-oxohexyl]-l,4,7,10-tetrazabicyclo[10.4.0]hexadecane-2,5,8,l 1-tetrone; and one or more pharmaceutically acceptable carriers.

[0053] Disclosed herein is a method of treating multiple sclerosis, the method comprising administering to the subject in need thereof a therapeutically effective amount of TD047 or a pharmaceutical formulation thereof. Disclosed herein is a method of treating multiple sclerosis, the method comprising administering to the subject in need thereof a therapeutically effective amount of TD047 or a pharmaceutical formulation thereof and administering one or more disclosed HDAC1 1 inhibitors or a pharmaceutical formulation thereof.

[0054] Disclosed herein is a method of treating a neurological disease and / or disorder, the method comprising administering to the subject in need thereof a therapeutically effective amount of a disclosed compound or a pharmaceutical formulation thereof.

[0055] Disclosed herein is a method of treating a neurological disease and / or disorder, the method comprising administering to the subject in need thereof a therapeutically effective amount of a disclosed compound of Formula (I) or a pharmaceutical formulation thereof,Formula (I), wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyd, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3, R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon, or a pharmaceutically acceptable salt thereof.GW173 (091019-869493)

[0056] Disclosed herein is a method of treating a neurological disease and / or disorder, the method comprising administering to the subject in need thereof a therapeutically effective amount of a disclosed compound of Formula (I) or a pharmaceutical formulation thereof,Formula (I); wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3, R3 can be hydrogen, polyalkydene oxide, or substituted amide, and * denotes can be a chiral carbon: with the proviso that the compound is not (3S,6S,9S,15aR)-6,9-Dibenzyl- 3-(6-oxo-6-((2S.3R)-3-undecyloxiran-2-yl)hexyl)octahydro-2H-pyrido[l, 2-a][l. 4, 7, 10]tetraazacyclododecine-l,4,7,10(3H,12H)-tetraone or (3S,65,9S,127?)-3,6-dibenzyl-9-[6-[(2 )- oxiran-2-yl]-6-oxohexyl]-l,4,7,10-tetrazabicyclo[10.4.0]hexadecane-2,5,8,l 1-tetrone; and one or more pharmaceutically acceptable carriers.

[0057] Disclosed herein is a method of treating a neurological disease and / or disorder, the method comprising administering to the subject in need thereof a therapeutically effective amount of TD047 or a pharmaceutical formulation thereof. Disclosed herein is a method of treating a neurological disease and / or disorder, the method comprising administering to the subject in need thereof a therapeutically effective amount of TD047 or a pharmaceutical formulation thereof and administering one or more disclosed HDAC11 inhibitors or a pharmaceutical formulation thereof.VII. DETAILED DESCRIPTION

[0058] The present disclosure describes formulations, compounded compositions, kits, capsules, containers, and / or methods thereof. It is to be understood that the inventive aspects of which are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may. of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

[0059] All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of theGW173 (091019-869493)present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.A. Definitions

[0060] Before the present compounds, compositions, articles, systems, devices, and / or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

[0061] This disclosure describes inventive concepts with reference to specific examples. However, the intent is to cover all modifications, equivalents, and alternatives of the inventive concepts that are consistent with this disclosure.

[0062] As used in the specification and the appended claims, the singular forms “a”. "an", and "the” include plural referents unless the context clearly dictates otherwise.

[0063] The phrase “consisting essentially of’ limits the scope of a claim to the recited components in a composition or the recited steps in a method as well as those that do not materially affect the basic and novel characteristic or characteristics of the claimed composition or claimed method. The phrase “consisting of’ excludes any component, step, or element that is not recited in the claim. The phrase “comprising” is synonymous with “including”, “containing”, or “characterized by”, and is inclusive or open-ended. “Comprising” does not exclude additional, unrecited components or steps.

[0064] In an aspect, when referring to any numerical value, the term “about” means a value falling within a range that is ± 10% of the stated value.

[0065] Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, a further aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about.” it will be understood that the particular value forms a further aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit betweenGW173 (091019-869493)two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0066] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

[0067] In an aspect, the terms "optional" or “optionally’' means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. In an aspect, a disclosed method can optionally comprise one or more additional steps, such as, for example, repeating an administering step or altering an administering step.

[0068] In an aspect, the term “subject” refers to the target of administration, e.g., a human being. The term “subject” also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc ), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.). Thus, the subject can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Alternatively, the subject of the herein disclosed methods can be a human, nonhuman primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not denote a particular age or sex, and thus, adult and child subjects, as well as fetuses, whether male or female, are intended to be covered. In an aspect, a subject can be a human patient. In an aspect, a subj ect can have cancer, be suspected of having cancer, or be at risk of developing cancer.

[0069] In an aspect, the term “diagnosed” means having been subjected to an examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by one or one or more disclosed HDAC11 inhibitors and / or one or more pharmaceutical formulations, or by one or more of the disclosed methods. For example, “diagnosed with a disease or disorder” means having been subjected to an examination by a person of skill, for example, a physician, and found to have a condition (such as cancer) that can be treated by one or one or more disclosed HDAC11 inhibitors and / or one or more pharmaceutical formulations, or by one or more of the disclosed methods. For example, “suspected of having a disease or disorder” can mean having been subjected to an examination by a person of skill, for example, a physician, and found to have a condition (such as cancer) that can likely be treated by one or one or more disclosed HD AC 11 inhibitors and / or one or more pharmaceutical formulations, or by one or more of the disclosed methods. In an aspect, an examination can be physical, can involve various tests (e.g.,GW173 (091019-869493)blood tests, genotyping, biopsies, etc.), scans (e.g., CT scans, PET scans, etc.), and assays (e.g., enzymatic assay), or a combination thereof.

[0070] In an aspect, a “patient” refers to a subject afflicted with a disease or disorder (e.g., cancer, MS, or a neurological disease or disorder). In an aspect, a patient can refer to a subject that has been diagnosed with or is suspected of having a disease or disorder such as cancer. In an aspect, a patient can refer to a subject that has been diagnosed with or is suspected of having a disease or disorder and is seeking treatment or receiving treatment for a disease or disorder (such as cancer).

[0071] In an aspect, the phrase “identified to be in need of treatment for a disease or disorder,” or the like, refers to selection of a subject based upon need for treatment of the disease or disorder. For example, a subject can be identified as having a need for treatment of a disease or disorder (e.g., cancer, MS, or a neurological disease or disorder) based upon an earlier diagnosis by a person of skill and thereafter subjected to treatment for the cancer, MS, or a neurological disease or disorder. In an aspect, the identification can be performed by a person different from the person making the diagnosis. In an aspect, the administration can be performed by one who performed the diagnosis.

[0072] In an aspect, “inhibit,” “inhibiting”, and “inhibition” mean to diminish or decrease an activity, level, response, condition, severity, disease, or other biological parameter. This can include, but is not limited to, the complete ablation of the activity, level, response, condition, severity, disease, or other biological parameter. This can also include, for example, a 10% inhibition or reduction in the activity, level, response, condition, severity, disease, or other biological parameter as compared to the native or control level (e.g., a subject not receiving one or one or more disclosed HDAC11 inhibitors and / or one or more pharmaceutical formulations). Thus, in an aspect, the inhibition or reduction can be a 10%. 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any amount of reduction in between as compared to native or control levels. In an aspect, the inhibition or reduction can be 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% as compared to a native or control level (e.g., a subject not receiving one or one or more disclosed HD AC 11 inhibitors and / or one or more pharmaceutical formulations). In an aspect, the inhibition or reduction can be 0-25%, 25-50%. 50-75%. or 75-100% as compared to native or control levels. In an aspect, a native or control level can be a predisease or pre-disorder level (such as a pre-cancer state).

[0073] The words “treat” or “treating” or “treatment” include palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, orGW173 (091019-869493)disorder; and supportive treatment, that is. treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. In an aspect, the terms cover any treatment of a subject, including a mammal e.g., a human), and includes: (i) preventing the undesired physiological change, disease, pathological condition, or disorder from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the physiological change, disease, pathological condition, or disorder, z.e., arresting its development; or (iii) relieving the physiological change, disease, pathological condition, or disorder, i.e., causing regression of the disease. For example, in an aspect, treating a disease or disorder can reduce the severity of an established a disease or disorder in a subject by 1 %-l 00% as compared to a control (such as, for example, an individual not having cancer, MS, or a neurological disease or disorder). In an aspect, treating can refer to a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of a disease or disorder (e.g., cancer, MS, or a neurological disease or disorder). For example, treating a disease or disorder can reduce one or more symptoms of a disease or disorder in a subject by l%-100% as compared to a control (such as, for example, an individual not having cancer, MS, or a neurological disease or disorder). In an aspect, treating can refer to 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%. 100% reduction of one or more symptoms of an established a disease or disorder (e.g., cancer, MS, or a neurological disease or disorder). It is understood that treatment does not necessarily refer to a cure or complete ablation or eradication of a disease or disorder. However, in an aspect, treatment can refer to a cure or complete ablation or eradication of a disease or disorder (e.g., cancer, MS, or a neurological disease or disorder).

[0074] In an aspect, the term “prevent’' or “preventing” or “prevention” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit, or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed. In an aspect, preventing a disease or disorder having chromatin deregulation and / or chromatin dysregulation is intended. The words “prevent”, “preventing”, and “prevention” also refer to prophylactic or preventative measures for protecting or precluding a subject (e.g., an individual) not having a given a disease or disorder (e.g., cancer, MS, or a neurological disease or disorder) or related complication from progressing to that complication. In an aspect, preventing metastasis is intended.

[0075] In an aspect, the terms “administering” and “administration” refer to any method of providing one or one or more disclosed HDAC11 inhibitors and / or one or more pharmaceuticalGW173 (091019-869493)formulations, disclosed anti-chemokines, disclosed anti-cancer agents, disclosed targeted therapies, disclosed chemotherapeutics, or a combination thereof. Such methods are well known to those skilled in the art and include, but are not limited to, the following: oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, in utero administration, intra-tumoral administration, intrahepatic administration, intravaginal administration, ophthalmic administration, intra-aural administration, otic administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-CSF administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can also include hepatic intraarterial administration or administration through the hepatic portal vein (HPV). Administration of a disclosed compound, a disclosed pharmaceutical formulation, a disclosed therapeutic agent, a disclosed immune modulator, a disclosed proteasome inhibitor, a disclosed small molecule, a disclosed endonuclease, a disclosed oligonucleotide, a disclosed RNA therapeutic, or any combination thereof can comprise administration directly into the CNS or the PNS. Administration can be continuous or intermittent. Administration can comprise a combination of one or more routes.

[0076] By “determining the amount'’ is meant both an absolute quantification of a particular analyte (e.g.. biomarker for cancer, MS. or a neurological disease or disorder) or a determination of the relative abundance of a particular analyte (e.g., biomarker for cancer, MS, or a neurological disease or disorder). The phrase includes both direct or indirect measurements of abundance or both.

[0077] In an aspect, the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile inj ectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. In an aspect, a pharmaceutical carrier employed can be a solid, liquid, or gas. In an aspect, examples of solid carriers can include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. In an aspect, examples of liquid carriers can include sugar syrup, peanut oil, olive oil, and water. In an aspect, examples of gaseous carriers can include carbon dioxide and nitrogen. In preparing a disclosed composition for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils,GW173 (091019-869493)alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly (anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial -retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.

[0078] In an aspect, the term “excipient” refers to an inert substance which is commonly used as a diluent, vehicle, preservative, binder, or stabilizing agent, and includes, but is not limited to, proteins (e.g., serum albumin, etc.), amino acids (e.g., aspartic acid, glutamic acid, lysine, arginine, glycine, histidine, etc ), fatty acids and phospholipids (e.g., alkyl sulfonates, caprylate, etc.), surfactants (e.g., SDS, polysorbate, nonionic surfactant, etc.), saccharides (e.g., sucrose, maltose, trehalose, etc.) and polyols (e.g., mannitol, sorbitol, etc.). See, also, for reference, Remington's Pharmaceutical Sciences, (1990) Mack Publishing Co., Easton, Pa., which is hereby incorporated by reference in its entirety.GW173 (091019-869493)

[0079] In an aspect, 'concurrently" means (1) simultaneously in time, or (2) at different times during the course of a common treatment schedule.

[0080] In an aspect, “contacting” refers to bringing one or one or more disclosed HDAC11 inhibitors and / or one or more pharmaceutical formulations, disclosed anti-chemokines, disclosed anti-cancer agents, disclosed targeted therapies, disclosed chemotherapeutics, or a combination thereof with a target area or intended target area in such a manner that one or one or more disclosed HDAC11 inhibitors and / or one or more pharmaceutical formulations, disclosed anti-chemokines, disclosed anti-cancer agents, disclosed targeted therapies, disclosed chemotherapeutics, or a combination thereof can exert an effect on the intended target or targeted area either directly or indirectly. A target area or intended target area can be one or more of a subject’s organs (e.g., lungs, heart, liver, kidney, brain, etc.) hosting cancerous cells expressing or over-expressing HDAC11 and / or YAP. In an aspect, a target area or intended target area can be any cell or any organ infected by a disease or disorder (such as cancer). In an aspect, a target area or intended target area can be any organ, tissue, or cells that are affected by a disease or disorder (such as cancer).

[0081] In an aspect, “determining” can refer to measuring or ascertaining the presence and severity of a disease or disorder, such as, for example, cancer or cancer cells expressing or overexpressing HDAC11 and / or YAP or cells expressing NCDN or any other disclosed protein. Methods and techniques used to determine the presence and / or severity of a disease or disorder are typically known to the medical arts. For example, the art is familiar with the ways to identify and / or diagnose the presence, severity, or both of a disease or disorder (e.g., cancer, MS, or a neurological disease or disorder).

[0082] In an aspect, “effective amount” and “amount effective” can refer to an amount that is sufficient to achieve the desired result such as, for example, the treatment and / or prevention of a disease or disorder (e.g., cancer, MS, or a neurological disease or disorder) or a suspected disease or disorder. In an aspect, the terms “effective amount” and “amount effective” can refer to an amount that is sufficient to achieve the desired an effect on an undesired condition (e.g., cancer, MS, or a neurological disease or disorder). For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects.

[0083] In an aspect, “therapeutically effective amount” means an amount of one or one or more disclosed HD AC 11 inhibitors and / or one or more pharmaceutical formulations, disclosed anti-chemokines, disclosed anti-cancer agents, disclosed targeted therapies, disclosed chemotherapeutics, or a combination thereof; that (i) treats the particular disease, condition, orGW173 (091019-869493)disorder (e.g., cancer, MS, or a neurological disease or disorder), (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder e.g., cancer), or (iii) delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein (e.g., cancer, MS, or a neurological disease or disorder). The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the disclosed HD AC 11 inhibitors and / or pharmaceutical formulations, disclosed anti-chemokines, disclosed anti-cancer agents, disclosed targeted therapies, disclosed chemotherapeutics, or any combination thereof employed; the disclosed methods employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of one or one or more disclosed HDAC11 inhibitors and / or one or more pharmaceutical formulations, disclosed anti-chemokines, disclosed anti-cancer agents, disclosed targeted therapies, disclosed chemotherapeutics, or any combination thereof employed; the duration of the treatment; drugs used in combination or coincidental with one or one or more disclosed HDAC11 inhibitors and / or one or more pharmaceutical formulations, disclosed anti-chemokines, disclosed anti-cancer agents, disclosed targeted therapies, disclosed chemotherapeutics, or a combination thereof employed, and other like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of one or one or more disclosed HDAC11 inhibitors and / or one or more pharmaceutical formulations, disclosed anti-chemokines. disclosed anti-cancer agents, disclosed targeted therapies, disclosed chemotherapeutics, or any combination thereof at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, then the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, a single dose of one or one or more disclosed HDAC11 inhibitors and / or one or more pharmaceutical formulations, disclosed anti-chemokines, disclosed anti-cancer agents, disclosed targeted therapies, disclosed chemotherapeutics, or any combination thereof can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition.

[0084] In an aspect, myelination is a complex process that is regulated on several levels. In diseases or disorders related to myelination, at least two distinct processes are involved. The firstGW173 (091019-869493)is the loss of myelination (e.g.. demyelination) while the second is the inhibition of remyelination. Compounds or treatments that slow or inhibit demyelination do not necessarily promote remyelination and vice versa.

[0085] Unless otherwise indicated, the following terms have the meanings set forth below.

[0086] In an aspect, the term “alkyl” refers to a straight-chain or branched hydrocarbon group containing the specified number of carbon atoms. Representative alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl.

[0087] In an aspect, the term “substituted alkyl” refers to an alkyl group substituted with one or more substituents selected from halogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, cyano, nitro, amide, ester, carboxyl, heterocycle, or aryl, wherein each substituent is optionally further substituted.

[0088] In an aspect, the term cycloalkyl refers to a saturated or partially unsaturated, monocyclic or bicyclic hydrocarbon group containing 3 to 8 ring carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. The cycloalkyl group may be optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, hydroxyl, amino, amide, cyano, or combinations thereof. In an aspect, the term “Cs-Cs cycloalk ’ refers to a saturated monocyclic hydrocarbon group containing 3 to 5 ring carbon atoms, including cyclopropyl, cyclobutyl, and cyclopentyl, optionally substituted as described herein. Cycloalkyl groups are non-aromatic.

[0089] In an aspect, the term “alkoxy” refers to an alky l group attached through an oxygen atom. Representative alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, and pentoxy.

[0090] In an aspect, the term “polyalkylene oxide” refers to a moiety comprising two or more repeating alky lene oxide units, including ethylene oxide, propylene oxide, or combinations thereof, which may be linear or branched and optionally terminated with hydrogen, alkyl, or functional groups.

[0091] In an aspect, the term “amide” refers to a — C(O)NR'R" group, wherein R' and R" are independently hydrogen or alkyl. A “substituted amide” refers to an amide group wherein one or more substituents are present on the nitrogen atom or the carbon backbone.

[0092] In an aspect, the term “pharmaceutically acceptable salt” refers to salts prepared from pharmaceutically acceptable acids or bases, including but not limited to hydrochloride, hydrobromide, sulfate, phosphate, acetate, citrate, maleate, fumarate, tartrate, lactate, mesylate, and besylate salts.GW173 (091019-869493)

[0093] The term ‘“immunotherapy” refers to the treatment of a subject afflicted with, or at risk of contracting or suffering a recurrence of, a disease by a method comprising inducing, enhancing, suppressing or otherwise modifying an immune response. Examples of immunotherapy can include, but are not limited to, NK cells and T cell therapies. T cell therapy can include adoptive T cell therapy, tumor-infiltrating lymphocyte (TIL) immunotherapy, autologous cell therapy, engineered autologous cell therapy (eACTTM), and allogeneic T cell transplantation. However, one of skill in the art would recognize that the conditioning methods disclosed herein would enhance the effectiveness of any transplanted T cell therapy. In an aspect, T cells or NK cells can come from any source known in the art. For example, T cells and NK cells can be differentiated in vitro from a hematopoietic stem cell population (for example iPSCs) or can be obtained from a subject. T cells and NK cells can be obtained from, e.g., peripheral blood mononuclear cells (PBMCs), bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. In addition, the T cells can be derived from one or more T cell lines available in the art. T cells can also be obtained from a unit of blood collected from a subject using any number of techniques known to the skilled artisan.

[0094] In an aspect, the term “autologous” refers to any material derived from the same individual to which it is later to be re-introduced.

[0095] In an aspect, the terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals in which a population of cells are characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More particular examples of such cancers include squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma and various types of head and neck cancer.

[0096] In an aspect, the terms “proliferative disorder” and “proliferative disease” refer to disorders associated with abnormal cell proliferation such as cancer.

[0097] In an aspect, “tumor” and “neoplasm” refer to any mass of tissue that result from excessive cell grow th or proliferation, either benign (noncancerous) or malignant (cancerous) including pre-cancerous lesions. “Metastasis” refers to the process by which a cancer spreads or transfers from the site of origin to other regions of the body with the development of a similar cancerous lesion at the new location. A “metastatic” or “metastasizing” cell is one that loses adhesive contacts withGW173 (091019-869493)neighboring cells and migrates via the bloodstream or lymph from the primary site of disease to invade neighboring body structures.

[0098] The terms “cancer stem cell” or “tumor stem cell” or “solid tumor stem cell” are used interchangeably herein and refer to a population of cells from a solid tumor that: (1) have extensive proliferative capacity; (2) are capable of asymmetric cell division to generate one or more kinds of differentiated progeny with reduced proliferative or developmental potential; and (3) are capable of symmetric cell divisions for self-renewal or self-maintenance. These properties of “cancer stem cells” or “tumor stem cells” or “solid tumor stem cells” confer on those cancer stem cells the ability to form palpable tumors upon serial transplantation into an immunocompromised mouse compared to the majority of tumor cells that fail to form tumors. Cancer stem cells undergo self-renewal versus differentiation in a chaotic manner to form tumors with abnormal cell types that can change over time as mutations occur.

[0099] In an aspect, “cancer cell” or “tumor cell” and grammatical equivalents refer to the total population of cells derived from a tumor including both non-tumorigenic cells, which comprise the bulk of the tumor cell population, and tumorigenic stem cells (cancer stem cells).

[0100] In an aspect, “tumorigenic” refers to the functional features of a solid tumor stem cell including the properties of self-renewal (giving rise to additional tumorigenic cancer stem cells) and proliferation to generate all other tumor cells (giving rise to differentiated and thus non-tumorigenic tumor cells) that allow solid tumor stem cells to form a tumor.

[0101] In an aspect, the “tumorigenicity” of a tumor refers to the ability of a random sample of cells from the tumor to form palpable tumors upon serial transplantation into immunocompromised mice.

[0102] In an aspect, “lipid nanoparticles” or “LNPs” can deliver nucleic acid (e.g., DNA or RNA), protein (e.g., RNA-guided DNA binding agent), or nucleic acid together with protein. LNPs can comprise biodegradable, ionizable lipids. For example, LNPs can comprise (9Z,12Z)-3-((4,4-bis(octyloxy)butanoyl)oxy)-2-((((3-(diethylamino)propoxy)carbonyl)oxy)methyl)propyl octadeca-9,12-di enoate, also called 3-((4,4-bis(octyloxy)butanoyl)oxy)-2-((((3- (diethylamino)propoxy)carbonyl)oxy)methyl)propyl (9Z.12Z)-octadeca-9,12-di enoate) or another ionizable lipid. In an aspect, the term cationic and ionizable in the context of LNP lipids can be use interchangeably, e.g., wherein ionizable lipids are cationic depending on the pH.

[0103] In an aspect, “sequence identity” and “sequence similarity” can be determined by alignment of two peptide or two nucleotide sequences using global or local alignment algorithms. Sequences may then be referred to as “substantially identical” or “essentially similar” when they are optimally aligned. For example, sequence similarity or identity can be determined byGW173 (091019-869493)searching against databases such as FASTA, BLAST, etc., but hits should be retrieved and aligned pairwise to compare sequence identify. Two proteins or two protein domains, or two nucleic acid sequences can have ‘‘substantial sequence identify” if the percentage sequence identify is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% or more, preferably 90%, 95%, 98%, 99% or more. Such sequences are also referred to as “variants” herein, e.g., other variants of a missing, deficient, and / or mutant protein or enzyme. It should be understood that sequence with substantial sequence identify do not necessarily have the same length and may differ in length. For example, sequences that have the same nucleotide sequence but of which one has additional nucleotides on the 3’-and / or 5 '-side are 100% identical.

[0104] In an aspect, “immune-modulating” refers to the ability of one or one or more disclosed HD AC 11 inhibitors and / or one or more pharmaceutical formulations, disclosed anti-chemokines, disclosed anti-cancer agents, disclosed targeted therapies, disclosed chemotherapeutics, or a combination thereof to alter (modulate) one or more aspects of the immune system. The immune system functions to protect the organism from infection and from foreign antigens by cellular and humoral mechanisms involving lymphocytes, macrophages, and other antigen-presenting cells that regulate each other by means of multiple cell-cell interactions and by elaborating soluble factors, including lymphokines and antibodies, that have autocrine, paracrine, and endocrine effects on immune cells.

[0105] In an aspect, “immune modulator” refers to an agent that is capable of adjusting a given immune response to a desired level (e.g., as in immunopotentiation, immunosuppression, or induction of immunologic tolerance). Examples of immune modulators include but are not limited to, a disclosed immune modulator can comprise aspirin, azathioprine, belimumab, betamethasone dipropionate, betamethasone valerate, bortezomib, bredinin, cyazathioprine. cyclophosphamide, cyclosporine, deoxy spergualin, didemnin B, fluocmolone acetonide, folinic acid, ibuprofen, 1L6 inhibitors (such as sarilumab) indomethacin, inebilizumab, intravenousy globulin (IVIG), methotrexate, methylprednisolone, mycophenolate mofetil, naproxen, prednisolone, prednisone, prednisolone indomethacin, rapamycin, rituximab, sirolimus, sulindac, synthetic vaccine particles containing rapamycin (SVP-Rapamycin or ImmTOR), thalidomide, tocilizumab. tolmetin, triamcinolone acetonide, anti-CD3 antibodies, anti-CD4 antibodies, anti-CD19 antibodies, anti-CD20 antibodies, anti-CD22 antibodies, anti-CD40 antibodies, anti-FcRN antibodies, anti-IL6 antibodies, anti-IGFIR antibodies, an IL2 mutein, a BTK inhibitor, or a combination thereof. In an aspect, a disclosed immune modulator can comprise one or more Treg (regulatory T cells) infusions (e.g., antigen specific Treg cells to AAV). In an aspect, a disclosed immune modulator can be bortezomib or SVP-Rapamycin. In an aspect, an immune modulator can be administeredGW173 (091019-869493)by any suitable route of administration including, but not limited to. in utero, intra-CSF, intrathecally, intravenously, subcutaneously, transdermally, intradermally, intramuscularly, orally, transcutaneously, intraperitoneally (IP), or intravaginally. In an aspect, a disclosed immune modulator can be administered using a combination of routes. Administration can also include hepatic intra-arterial administration or administration through the hepatic portal vein (HPV). Administration of an immune modulator can be continuous or intermittent, and administration can comprise a combination of one or more routes.

[0106] In an aspect, the term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and / or warnings concerning the use of such therapeutic products.

[0107] In an aspect, the term “in combination” in the context of the administration of other therapies (e.g., other agents) includes the use of more than one therapy (e.g., drug therapy). Administration “in combination with” one or more further therapeutic agents includes simultaneous (e.g., concurrent) and consecutive administration in any order. The use of the term “in combination” does not restrict the order in which therapies are administered to a subject. By way of non-limiting example, a first therapy (e.g., one or one or more disclosed HD AC 11 inhibitors and / or one or more pharmaceutical formulations, disclosed anti-chemokines, disclosed anti-cancer agents, disclosed targeted therapies, disclosed chemotherapeutics, or a combination thereof) can be administered prior to (e.g., 1 minute, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks), concurrently, or after (e.g., 1 minute, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours. 7 hours, 8 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks or longer) the administration of a second therapy to a subject having or diagnosed with cancer.

[0108] Disclosed are the components to be used to prepare one or one or more disclosed HDAC11 inhibitors and / or one or more pharmaceutical formulations, disclosed anti-chemokines, disclosed anti-cancer agents, disclosed targeted therapies, disclosed chemotherapeutics, or a combination thereof as well as one or one or more disclosed HD AC 11 inhibitors and / or one or more pharmaceutical formulations, disclosed anti-chemokines. disclosed anti-cancer agents, disclosed targeted therapies, disclosed chemotherapeutics, or a combination thereof used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that whenGW173 (091019-869493)combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations. A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific aspects or combination of aspects of the methods of the invention.B. Histone Deactylase 11 (HDAC11)

[0109] The histone deacetylase (HDAC) family members are widely involved in important biological processes such as gene expression regulation and chromatin modification. HDAC11 is a newly discovered member of the HDAC family, and its encoding gene is located in the chromosome arm 3p25, and its promoter lacks the canonical TATA and CCAAT boxes. HDAC 11 is mainly located in the nucleus and cytoplasm of cells and can affect cell behavior through different mechanisms. HDAC 11 can interact with certain histones, transcription factors, and ncRNAs to affect gene expression.

[0110] In an aspect, HDAC 11 can be identified by various accession numbers including HGNC (19086), NCBI Gene (79885), Ensembl (ENSG00000163517), OMIM® (607226), and UniProtKB / Swiss-Prot (Q96DB2). HDAC11, comprised of 347 amino acids, stands as the smallest known HDAC member. It is worth noting that approximately 80% of its protein sequence is dedicated to the HDAC catalytic domain. In contrast, its N- and C-terminal extensions are relatively small and do not contain any predicted protein binding sites. The catalytic channel structure, which exhibits a funnel shape, is conserved across HDACs. The enlargement of the funnel-shaped catalytic channel in HDAC 11 enables it to acquire fatty acid deacylase activity, establishing HDAC 11 as the most proficient member with regards to fatty acid deacylation within the HDAC family. The variable loop 2 (L2) plays a crucial role in substrate recognition andGW173 (091019-869493)catalysis in HDACs. AspIO I. located at the entrance of the tunnel, is the only conserved amino acid in the L2 of class I and class II HDACs. Substitution of AsplOl in HDAC4 and HDAC8 almost completely abolishes their deacetylase activity’.

[0111] The role of HDAC11 in cancer is complex. There are reports on HDAC11 expression in various cancer types, though some findings appear contradictory. Thus, the role of HD AC 11 in cancer appears to be context-dependent. While HD AC 11 expression is significantly increased and promotes cancer progression in some malignancies, it is decreased and inhibits progression in others, indicating that its function may vary by cancer type. For example, HD AC 11 expression was high in breast cancer, cholangiocarcinoma, colon adenocarcinoma, diffuse large B-cell lymphoma, kidney chromophobe, liver hepatocellular carcinoma, lung adenocarcinoma, pheochromocytoma and paraganglioma, rectal adenocarcinoma, and thymoma (Li R, et al. (2022) FASEB J. 36(7):e22326). In another series of studies, there was significant upregulation of HDAC11 expression in lung cancer (Lu D, et al. (2022) Transl Lung Cancer Res. 11(6): 1119-1131), liver cancer (Bi L, et al. (2021) Cancer Res. 81(8):2015-2028), and breast cancer (Zhao H, et al. (2023) Int J Clin Exp Pathol. 16(7): 172-183) patient samples when compared to normal tissue (i.e., corresponding tissue taken for a patient not having cancer).C. YES1 Associated Transcriptional Regulator (Y P1)

[0112] YAP1 encodes a downstream nuclear effector of the Hippo signaling pathway which is involved in development, growth, repair, and homeostasis. YAP1 is known to play a role in the development and progression of multiple cancers as a transcriptional regulator of this signaling pathway and may function as a potential target for cancer treatment. Alternative splicing results in multiple transcript variants encoding different isoforms. YAP1 is also known as YAP, YKI, COB1. YAP2, YAP-1, and YAP65.

[0113] In an aspect, YAP1 can be identified by various accession numbers including HGNC (16262), NCBI Gene (10413), Ensembl (ENSG00000137693), OMIM® (606608), and UniProtKB / Swiss-Prot (P46937). In an aspect, YAP1 can comprise a sequence having at least 50% identity, at least 55% identity, at least 60% identity, at least 65% identity, at least 70% identity, at least 75% identity, at least 80% identity, at least 85% identity, at least 90% identity, at least 95% identity, or more than 95% identity to the sequence set forth in with HGNC (16262), NCBI Gene (10413), Ensembl (ENSG00000137693), OMIM® (606608), or UniProtKB / Swiss-Prot (P46937) or a portion thereof or a fragment thereof. In an aspect, YAP1 can comprise the sequence set forth in NCBI Ref. No. NG 029530.2 or a portion thereof or a fragment thereof. In an aspect, YAP1 can comprise the sequence set forth in NCBI Ref. No. NM_001130145.3 or a portion thereof or a fragment thereof. In an aspect, YAP1 can comprise the sequence set forth inGW173 (091019-869493)NCBI Ref. No. NP_001123617.1 or a portion thereof or a fragment thereof. In an aspect YAP1 can comprise the sequence set forth in SEQ ID NO: 11 or a portion thereof or a fragment thereof. In an aspect, YAP1 can comprise the sequence set forth in SEQ ID NO: 12 or a portion thereof or a fragment thereof. In an aspect, YAP1 can comprise the sequence set forth in SEQ ID NO: 13 or a portion thereof or a fragment thereof.D. Neurochondrin / Norbin (NCDN)

[0114] Neurochondrin / Norbin (NCDN) encodes a leucine-rich cytoplasmic protein, which is highly similar to a mouse protein that negatively regulates Ca / calmodulin-dependent protein kinase II phosphorylation and may be essential for spatial learning processes. Several alternatively spliced transcript variants of this gene have been described.

[0115] In an aspect, Neurochondrin / Norbin (NCDN) can be identified by various accession numbers including HGNC (17597), NCBI Gene (23154), Ensembl (ENSG00000020129), OMIM® (608458), and UniProtKB / Swiss-Prot (Q9UBB6). In an aspect, NCDN can comprise a sequence having at least 50% identity, at least 55% identity, at least 60% identity, at least 65% identity, at least 70% identity, at least 75% identity, at least 80% identity, at least 85% identity, at least 90% identity, at least 95% identity, or more than 95% identity to the sequence set forth in with HGNC (17597), NCBI Gene (23154), Ensembl (ENSG00000020129), OMIM® (608458), and UniProtKB / Swiss-Prot (Q9UBB6) or a portion thereof or a fragment thereof. In an aspect, NCDN can comprise the sequence set forth in NCBI Ref. No. NC 000001.11 or a portion thereof or a fragment thereof. In an aspect, NCDN can comprise the sequence set forth in NCBI Ref. No. NM_001014839.2 or a portion thereof or a fragment thereof. In an aspect, NCDN can comprise the sequence set forth in NCBI Ref. No. NP_001014839.1 or a portion thereof or a fragment thereof. In an aspect, NCDN can comprise the sequence set forth in SEQ ID NO: 35 or a portion thereof or a fragment thereof. In an aspect, NCDN can comprise the sequence set forth in SEQ ID NO:36 or a portion thereof or a fragment thereof. In an aspect, NCDN can comprise the sequence set forth in SEQ ID NO:37 or a portion thereof or a fragment thereof.E. Compositions1. HD AC 11 Inhibitors

[0116] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof:GW173 (091019-869493)Formula (I), wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3, R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon.

[0117] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof:Formula (I); wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3, R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon; with the proviso that the compound is not (3S,6S,9S,15aR)-6,9-Dibenzyl- 3-(6-oxo-6-((2S,3R)-3-undecyloxiran-2-yl)hexyl)octahydro-2H-pyrido[l, 2-a][l, 4, 7, 10]tetraazacyclododecine-1.4.7.10(3H,12H)-tetraone or (3S,65’,95.127?)-3.6-dibenzyl-9-[6-[(25 - oxiran-2-yl]-6-oxohexyl]-l,4,7,10-tetrazabicyclo[10.4.0]hexadecane-2,5,8,ll-tetrone.

[0118] In an aspect, a disclosed n can be an integer from 1 to about 6. In an aspect, a disclosed n can be 1, 2, 3, 4, or 5. In an aspect, a disclosed n can be 1. In an aspect, a disclosed n can be 2. In an aspect, a disclosed n can be 3. In an aspect, a disclosed n can be 4. In an aspect, a disclosed n can be 5. In an aspect, a disclosed n can be 6.

[0119] In an aspect, Ri can be C1-C15 alkyl or substituted alkyl. In an aspect, a disclosed substituted alk l in Ri can be substituted with one or more halogens or one or more hydroxy.

[0120] In an aspect, a disclosed halogen can be fluorine, chloride, bromine, or iodine.GW173 (091019-869493)

[0121] In an aspect, Ri can be a C3-C5 substituted cycloalkyl. In an aspect. Ri may be a cyclopropyl, a substituted cyclopropyl, a cyclobutyl, a substituted cyclobutyl, a cyclopentyl, or a substituted cyclopenyl.

[0122] In an aspect, a disclosed cycloalkyl may be substituted wi th one or more halogens. For example, in an aspect, the cycloalkyl may be substituted with one or more of fluorine, chlorine, bromine, or iodine. In an aspect, a disclosed cycloalkyl can be substituted with a substituted Ci-Ce alkyl. In an aspect, a substituted alkyl can be substituted with one or more halogens or one or more hydroxy. For example, in an aspect, the substituted alkyl can be -CF3, -CHF2, -CH2F -CCI3, -CHCh, -CH2CI, -CBr3, -CHBr2, -CH2Br -COH3, -CHOH2, or -CH2OH. In an aspect, Ri can be C3-C5 substituted heterocyclyl. In an aspect, a disclosed heterocyclyl can be substituted with a C1-C12 alkyl or a C1-C12 substituted alkyl.

[0123] In an aspect, Ri can be a substituted oxirane or a substituted 1,3-dioxolane. In an aspect, Ri can beinteger from 1 to 10. In an aspect, a disclosed m can be 1. In an aspect, a disclosed m can be 2. In an aspect, a disclosed m can be 3. In an aspect, a disclosed m can be 4. In an aspect, a disclosed m can be 5. In an aspect, a disclosed m can be 6. In an aspect, a disclosed m can be 7. In an aspect, a disclosed m can be 8. In an aspect, a disclosed m can be 9. In an aspect, a disclosed m can be 10.

[0124] In an aspect, R2 can be a hydrogen -OR3.

[0125] In an aspect, R3 can be polyalkylene oxide. Polyalkylene oxide can be considered a subset of alkoxy-containing substituents. For example, in an aspect, a disclosed alkoxy-containing substituent can include ethylene oxide units. In an aspect, a disclosed polyalkylene oxide can be -(CH2-CH2-O)3-CH3. In an aspect, incorporation of a polyalkylene oxide moiety can improve one or more properties selected from aqueous solubility, metabolic stability, cellular permeability, or target engagement.

[0126] In an aspect, a disclosed compound can be any one of:GW173 (091019-869493)

[0127] In an aspect, a disclosed compound can be synthesized using standard peptide coupling, alkylation, ether formation, epoxidation, and functional group interconversion techniques known in the art. Chiral centers may be introduced using enantioselective synthesis or resolved using conventional methods. Polyalkylene oxide substituents may be introduced prior to or subsequent to macrocycle formation. Polyalkylene oxide moieties may be introduced via ether formation,GW173 (091019-869493)nucleophilic substitution, or coupling reactions using appropriately functionalized intermediates. Protection and deprotection strategies may be employed as necessary.

[0128] Unless otherwise stated, individual embodiments and substituent definitions described herein may be combined in any manner consistent with the disclosed structures.

[0129] Disclosed herein is TD047. Disclosed herein is TD048.

[0130] In an aspect, a disclosed pharmaceutical formulation can treat cancer. In an aspect, a disclosed pharmaceutical formulation can slow disease progression. In an aspect, a disclosed pharmaceutical formulation can reduce tumor growih and migration. In an aspect, a disclosed pharmaceutical formulation can reduce and / or inhibit tumor cell proliferation and / or tumor cell migration. In an aspect, a disclosed pharmaceutical formulation can decrease and / or suppress tumor growth. In an aspect, a disclosed pharmaceutical formulation can decrease and / or suppress tumor growth as evidenced by a decreased volume and / or decreased tumor weight. In an aspect, a disclosed pharmaceutical formulation can protect the subject from metastasis. In an aspect, a disclosed pharmaceutical formulation can reduce the risk of developing metastasis. In an aspect, a disclosed pharmaceutical formulation can prevent or inhibit metastasis. In an aspect, a disclosed pharmaceutical formulation can comprise reducing viability of one or more cancer cells.

[0131] In an aspect, a disclosed pharmaceutical formulation can (i) prolong the subject’s survivability, (ii) increase the length of time before metastasis, (iii) reduce the risk of metastases, (iv) reduce the likelihood of surgical intervention, (v) reduce the need for administration of one or more additional therapeutic agents or regimens, (vi) reduce the size of one or more tumors in the subject, (vii) eliminate and / or reduce the size of one or more tumors in the subject, (viii) reduce or eliminate the prevalence of one or more genomic aberrations, (ix) restore the normal metabolism of one or more organ systems in the subject, (x) restore one or more aspect of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation, (xi) reduce and / or inhibit aberrant angiogenesis and / or vasculogenesis in one or more tissues and / or organs of the subject, (xii) decrease and / or suppress tumor growth, (xiii) ameliorate and / or eliminate one or more symptoms associated with the subject’s cancer, (xiv) delay the onset of one or more symptoms of the subject’s cancer, (xv) decrease and / or diminish tumor cell migration, (xvi) decrease and / or diminish tumor cell proliferation, or (xvii) any combination thereof.

[0132] In an aspect, a disclosed pharmaceutical formulation can be used in a disclosed method. In an aspect, a disclosed pharmaceutical formulation can be used in a method of treating ovarian cancer, ovarian adenocarcinoma, ovarian teratocarcinoma, lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous cell lung carcinoma, adenocarcinoma, gastric cancer, breast cancer, hepatic cancer, pancreatic cancer, skin cancer, in particular basal cellGW173 (091019-869493)carcinoma and squamous cell carcinoma, malignant melanoma, head and neck cancer, malignant pleomorphic adenoma, sarcoma, synovial sarcoma, carcinosarcoma, bile duct cancer, bladder cancer, transitional cell carcinoma, papillary carcinoma, kidney cancer, renal cell carcinoma, clear cell renal cell carcinoma, papillary renal cell carcinoma, colon cancer, small bowel cancer, small bowel adenocarcinoma, adenocarcinoma of the ileum, testicular embryonal carcinoma, placental choriocarcinoma, cervical cancer, testicular cancer, testicular seminoma, testicular teratoma, embryonic testicular cancer, uterine cancer, teratocarcinoma, embryonal carcinoma, or any combination thereof.

[0133] In an aspect, a disclosed pharmaceutical formulation can improve the life expectancy of the subject. In an aspect, a disclosed pharmaceutical formulation can improve life expectancy compared to the cancer life expectancy of an untreated subject with the identical or near identical disease condition and the identical or near identical predicted outcome. In an aspect, a disclosed pharmaceutical formulation can result in a reduction in size of a tumor. In an aspect, a disclosed pharmaceutical formulation can result in a reduction in tumor volume. In an aspect, a disclosed pharmaceutical formulation can result in a decrease in number of tumors. In an aspect, a disclosed pharmaceutical formulation can result in a decrease in number of metastatic lesions in other tissues or organs distant from the primary tumor site. In an aspect, a disclosed pharmaceutical formulation can result in an increase in survival time of a treated subject when, for example, compared to a subject not receiving treatment. In an aspect, a disclosed pharmaceutical formulation can decrease the mortality rate of a population of treated subjects in comparison to a population not receiving treatment. In an aspect, a disclosed pharmaceutical formulation can result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. In an aspect, a disclosed pharmaceutical formulation can result in a decrease in tumor growth rate. In an aspect, a disclosed pharmaceutical formulation can improve and / or extend the survivability of the subject, can improve a subject’s quality of life, can increase and / or prolong a subject’s life span, or any combination thereof. In an aspect, a disclosed pharmaceutical formulation can stimulate an effector cell mediated immune modulator response to tumor cells. In an aspect, a disclosed pharmaceutical formulation can induce a tumor reducing immune response. In an aspect, a disclosed pharmaceutical formulation can induce phagocytosis of cancer cells in the subject. In an aspect, a disclosed pharmaceutical formulation can cross-prime an antitumor T cell response. In an aspect, a disclosed method of treating cancer can induce a tumor eliminating immune response. In an aspect, a disclosed pharmaceutical formulation can decrease and / or suppress tumor growth.GW173 (091019-869493)

[0134] In an aspect, a disclosed pharmaceutical formulation can prevent and / or hinder fatty acylation of YAP by HD AC 11. In an aspect, a disclosed pharmaceutical formulation can prevent and / or hinder lysine fatty acylation of KI 81 and K254 of YAP by HDAC11. In an aspect, a disclosed pharmaceutical formulation can disrupt and / or decrease the nuclear localization of YAP. In an aspect, a disclosed pharmaceutical formulation, nuclear localization of YAP can be disrupted and / or decreased. In an aspect, a disclosed pharmaceutical formulation can decrease and / or diminish expression of HDAC11 by one or more cancer cells. In an aspect, a disclosed pharmaceutical formulation can decrease and / or diminish expression of HD AC 11 by one or more cancer cells, which can correlate with improved patient survival.

[0135] In an aspect, a disclosed pharmaceutical formulation can suppress, reduce, and / or inhibit YAP. In an aspect, a disclosed pharmaceutical formulation can suppress and / or inhibit YAP-dependent transcription programs. In an aspect, a disclosed pharmaceutical formulation can suppress, reduce, and / or inhibit HDAC11 expression and / or activity. In an aspect, a disclosed pharmaceutical formulation can suppress, reduce, and / or inhibit lysine fatty acylation of YAP. In an aspect, a disclosed pharmaceutical formulation can suppress, reduce, and / or inhibit lysine fatty acylation of YAP can occur at WW domains K181 and / or K254. In an aspect, following the administering of a disclosed pharmaceutical formulation, fatty acylation at KI 81 can promote CRM 1 -mediated nuclear export. In an aspect, following the administering of a disclosed pharmaceutical formulation, fatty acylation at K254 can facilitate ubiquitination and proteasomal degradation.

[0136] In an aspect, a disclosed pharmaceutical formulation can dysregulate the expression and / or activity of YAP. In an aspect, a disclosed pharmaceutical formulation can normalize the level of YAP expression and / or YAP activity. In an aspect, a disclosed pharmaceutical formulation can cause the level of YAP expression and / or YAP activity to be that of a control cell and / or a control tissue, or can return the level of YAP expression and / or YAP activity to a control cell level and / or a control tissue level.

[0137] In an aspect, a disclosed pharmaceutical formulation can enhance YAP-CRM1 interaction. In an aspect, a disclosed pharmaceutical formulation can enhance YAP-CRM1 interaction, thereby increasing nuclear export of YAP. In an aspect, a disclosed pharmaceutical formulation can destabilize YAP. In an aspect, a disclosed pharmaceutical formulation can reduce YAP transcriptional output. In an aspect, a disclosed pharmaceutical formulation can increase ubiquitin-mediated proteasomal degradation. In an aspect, a disclosed pharmaceutical formulation can increase ubiquitin-mediated proteasomal degradation of YAP. In an aspect, a disclosed pharmaceutical formulation can increase and / or facilitate CRM1 -mediated nuclearGW173 (091019-869493)export of YAP. In an aspect, a disclosed pharmaceutical formulation can disrupt the HDAC11-YAP axis in one or more cancerous cells. In an aspect, a disclosed pharmaceutical formulation can disrupt oncogenic YAP signaling. In an aspect, a disclosed pharmaceutical formulation can treat cancer without altering global histone acetylation or global tubulin acetylation.

[0138] In an aspect, a disclosed pharmaceutical formulation can be used to treat a YAP-driven cancer in a subject. In an aspect, a disclosed pharmaceutical formulation can be used to treat a YAP-driven malignancy in a subject. In an aspect, a disclosed pharmaceutical formulation can be used to treat a cancer having a YAP-driven tumorigenic profile.

[0139] In an aspect, a disclosed pharmaceutical formulation can be used to treat a cancer characterized by HDAC11 overexpression. In an aspect, a disclosed pharmaceutical formulation can be used to treat a cancer characterized by a HD AC 11 overexpression driven malignancy in a subject. In an aspect, a disclosed pharmaceutical formulation can be used to treat a cancer having a HDAC11 overexpression driven tumorigenic profile. In an aspect, a disclosed pharmaceutical formulation can target cancer cells characterized by HD AC 11 overexpression. In an aspect, a disclosed pharmaceutical formulation can target cancer cells characterized by HD AC 11 overexpression and increased lipid flux. In an aspect, a disclosed pharmaceutical formulation can target HD AC 11 -overexpressing cancer cells. In an aspect, a disclosed pharmaceutical formulation can target HDAC11 -overexpressing cancer cells having increased lipid flux.

[0140] In an aspect, TD047 can treat cancer. In an aspect, TD047 can slow disease progression. In an aspect, TD047 can reduce tumor growth and migration. In an aspect, TD047 can reduce and / or inhibit tumor cell proliferation and / or tumor cell migration. In an aspect, TD047 can decrease and / or suppress tumor grow th. In an aspect, TD047 can decrease and / or suppress tumor growth as evidenced by a decreased volume and / or decreased tumor weight. In an aspect, TD047 can protect the subject from metastasis. In an aspect, TD047 can reduce the risk of developing metastasis. In an aspect, TD047 can prevent or inhibit metastasis. In an aspect, TD047 can comprise reducing viability of one or more cancer cells.

[0141] In an aspect, TD047 can (i) prolong the subject’s survivability, (ii) increase the length of time before metastasis, (iii) reduce the risk of metastases, (iv) reduce the likelihood of surgical intervention, (v) reduce the need for administration of one or more additional therapeutic agents or regimens, (vi) reduce the size of one or more tumors in the subject, (vii) eliminate and / or reduce the size of one or more tumors in the subject, (viii) reduce or eliminate the prevalence of one or more genomic aberrations, (ix) restore the normal metabolism of one or more organ systems in the subject, (x) restore one or more aspect of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation, (xi) reduce and / or inhibit aberrant angiogenesis and / orGW173 (091019-869493)vasculogenesis in one or more tissues and / or organs of the subject, (xii) decrease and / or suppress tumor growth, (xiii) ameliorate and / or eliminate one or more symptoms associated with the subject’s cancer, (xiv) delay the onset of one or more symptoms of the subject’s cancer, (xv) decrease and / or diminish tumor cell migration, (xvi) decrease and / or diminish tumor cell proliferation, or (xvii) any combination thereof.

[0142] In an aspect, TD047 can be used in a disclosed method. In an aspect, TD047 can be used in a method of treating ovarian cancer, ovarian adenocarcinoma, ovarian teratocarcinoma, lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous cell lung carcinoma, adenocarcinoma, gastric cancer, breast cancer, hepatic cancer, pancreatic cancer, skin cancer, in particular basal cell carcinoma and squamous cell carcinoma, malignant melanoma, head and neck cancer, malignant pleomorphic adenoma, sarcoma, synovial sarcoma, carcinosarcoma, bile duct cancer, bladder cancer, transitional cell carcinoma, papillary carcinoma, kidney cancer, renal cell carcinoma, clear cell renal cell carcinoma, papillary7renal cell carcinoma, colon cancer, small bowel cancer, small bowel adenocarcinoma, adenocarcinoma of the ileum, testicular embryonal carcinoma, placental choriocarcinoma, cervical cancer, testicular cancer, testicular seminoma, testicular teratoma, embryonic testicular cancer, uterine cancer, teratocarcinoma, embryonal carcinoma, or any combination thereof.

[0143] In an aspect, TD047 can improve the life expectancy of the subject. In an aspect, TD047 can improve life expectancy compared to the cancer life expectancy of an untreated subject with the identical or near identical disease condition and the identical or near identical predicted outcome. In an aspect, TD047 can result in a reduction in size of a tumor. In an aspect, TD047 can result in a reduction in tumor volume. In an aspect, TD047 can result in a decrease in number of tumors. In an aspect. TD047 can result in a decrease in number of metastatic lesions in other tissues or organs distant from the primary tumor site. In an aspect, TD047 can result in an increase in survival time of a treated subject when, for example, compared to a subject not receiving treatment. In an aspect, TD047 can decrease the mortality7rate of a population of treated subjects in comparison to a population not receiving treatment. In an aspect, TD047 can result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. In an aspect, TD047 can result in a decrease in tumor growth rate. In an aspect, TD047 can improve and / or extend the survivability7of the subject, can improve a subject’s quality of life, can increase and / or prolong a subject’s life span, or any combination thereof. In an aspect, TD047 can stimulate an effector cell mediated immune modulator response to tumor cells. In an aspect, TD047 can induce a tumor reducing immune response. In an aspect, TD047 can induce phagocytosis of cancer cells in the subject. In an aspect, TD047 can cross-prime an anti -tumor TGW173 (091019-869493)cell response. In an aspect, a disclosed method of treating cancer can induce a tumor eliminating immune response. In an aspect, TD047 can decrease and / or suppress tumor growth.

[0144] In an aspect, TD047 can prevent and / or hinder fatty acylation of YAP by HDAC11. In an aspect, TD047 can prevent and / or hinder lysine fatty acylation of K181 and K254 of YAP by HDAC11. In an aspect, TD047 can disrupt and / or decrease the nuclear localization of YAP. In an aspect, TD047. nuclear localization of YAP can be disrupted and / or decreased. In an aspect, TD047 can decrease and / or diminish expression of HD AC 11 by one or more cancer cells. In an aspect, TD047 can decrease and / or diminish expression of HD AC 11 by one or more cancer cells, which can correlate with improved patient survival.

[0145] In an aspect. TD047 can suppress, reduce, and / or inhibit YAP. In an aspect, TD047 can suppress and / or inhibit YAP-dependent transcription programs. In an aspect, TD047 can suppress, reduce, and / or inhibit HDAC11 expression and / or activity. In an aspect, TD047 can suppress, reduce, and / or inhibit lysine fatty7acylation of YAP. In an aspect, TD047 can suppress, reduce, and / or inhibit lysine fatty7acylation of YAP can occur at WW domains KI 81 and / or K254. In an aspect, following the administering of TD047, fatty acylation at K181 can promote CRM1-mediated nuclear export. In an aspect, following the administering of TD047, fatty7acylation at K254 can facilitate ubiquitination and proteasomal degradation.

[0146] In an aspect, TD047 can dysregulate the expression and / or activity of YAP. In an aspect, TD047 can normalize the level of YAP expression and / or YAP activity. In an aspect, TD047 can cause the level of YAP expression and / or YAP activity to be that of a control cell and / or a control tissue, or can return the level of YAP expression and / or YAP activity to a control cell level and / or a control tissue level.

[0147] In an aspect, TD047 can enhance YAP-CRM1 interaction. In an aspect. TD047 can enhance YAP-CRM1 interaction, thereby increasing nuclear export of YAP. In an aspect, TD047 can destabilize YAP. In an aspect, TD047 can reduce YAP transcriptional output. In an aspect, TD047 can increase ubiquitin-mediated proteasomal degradation. In an aspect, TD047 can increase ubiquitin-mediated proteasomal degradation of YAP. In an aspect, TD047 can increase and / or facilitate CRMl-mediated nuclear export of YAP. In an aspect, TD047 can disrupt the HDAC11-YAP axis in one or more cancerous cells. In an aspect, TD047 can disrupt oncogenic YAP signaling. In an aspect, TD047 can treat cancer without altering global histone acetylation or global tubulin acetylation.

[0148] In an aspect, TD047 can be used to treat a YAP-driven cancer in a subject. In an aspect, TD047 can be used to treat a YAP-driven malignancy in a subject. In an aspect, TD047 can be used to treat a cancer having a YAP-driven tumorigenic profile.GW173 (091019-869493)

[0149] In an aspect, TD047 can be used to treat a cancer characterized by HDAC11 overexpression. In an aspect, TD047 can be used to treat a cancer characterized by a HDAC11 overexpression driven malignancy in a subject. In an aspect, TD047 can be used to treat a cancer having a HD AC 11 overexpression driven tumorigenic profile. In an aspect, TD047 can target cancer cells characterized by HD AC 11 overexpression. In an aspect. TD047 can target cancer cells characterized by HDAC11 overexpression and increased lipid flux. In an aspect, TD047 can target HD AC 11 -overexpressing cancer cells. In an aspect, TD047 can target HDAC11-overexpressing cancer cells having increased lipid flux.

[0150] In an aspect, a disclosed compound can increase and / or enhance the efficacy of one or more anti-cancer therapies administered to the subject. In an aspect, a disclosed HD AC 11 inhibitor can increase and / or enhance the efficacy of one or more anti-cancer therapies administered to the subject. In an aspect, TD047 can increase and / or enhance the efficacy of one or more anti-cancer therapies administered to the subj ect.

[0151] In an aspect, a disclosed compound can be used to treat multiple sclerosis, be used to slow disease progression of multiple sclerosis, alleviate and / or ameliorate one or more symptoms of multiple sclerosis, or any combination thereof. In an aspect, TD047 can be used to treat multiple sclerosis, be used to slow disease progression of multiple sclerosis, alleviate and / or ameliorate one or more symptoms of multiple sclerosis, or any combination thereof.

[0152] In an aspect, a disclosed compound can improve and / or ameliorate one or more symptoms associated with MS including but not limited to i) vision problems, such as double vision or optic neuritis (inflammation of the optic nerve), which causes pain with eye movement and vision loss; (ii) muscle weakness, often in the arms and legs, and muscle stiffness with painful muscle spasms; (iii) tingling, numbness, or pain in the arms, legs, trunk, or face; (iv) clumsiness, especially difficulty staying balanced when walking; (v) bladder control problems; (vi) intermittent or constant dizziness; (vii) mental or physical fatigue; (viii) mood changes such as depression or difficulty with emotional expression or control; (ix) cognitive changes (e.g., problems concentrating, multitasking, thinking, or learning, or difficulties with memory' or judgment), or (x) any combination thereof.

[0153] In an aspect, TD047 can improve and / or ameliorate one or more symptoms associated w ith MS including but not limited to i) vision problems, such as double vision or optic neuritis (inflammation of the optic nerve), which causes pain with eye movement and vision loss; (ii) muscle weakness, often in the arms and legs, and muscle stiffness with painful muscle spasms; (iii) tingling, numbness, or pain in the arms, legs, trunk, or face; (iv) clumsiness, especially difficulty' staying balanced when walking; (v) bladder control problems; (vi) intermittent orGW173 (091019-869493)constant dizziness; (vii) mental or physical fatigue; (viii) mood changes such as depression or difficulty with emotional expression or control; (ix) cognitive changes (e.g., problems concentrating, multitasking, thinking, or learning, or difficulties with memory or judgment), or (x) any combination thereof.

[0154] In an aspect, a disclosed compound can be used to treat a neurological disease and / or disorder, be used to slow disease progression of a neurological disease and / or disorder, alleviate and / or ameliorate one or more symptoms of a neurological disease and / or disorder, or any combination thereof. In an aspect, TD047 can be used to treat a neurological disease and / or disorder, be used to slow disease progression of a neurological disease and / or disorder, alleviate and / or ameliorate one or more symptoms of a neurological disease and / or disorder, or any combination thereof.

[0155] In an aspect, a disclosed compound can be encapsulated in lipid nanoparticles. In an aspect, TD047 can be encapsulated in lipid nanoparticles.2. Pharmaceutical Formulations

[0156] Disclosed herein is a pharmaceutical formulation comprising a disclosed compound and one or more pharmaceutically acceptable carriers.

[0157] Disclosed herein is a pharmaceutical formulation comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof:Formula (I), wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3, R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon: and one or more pharmaceutically acceptable carriers.

[0158] Disclosed herein is a pharmaceutical formulation comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof:GW173 (091019-869493)Formula (I); wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3, R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon: with the proviso that the compound is not (3S,6S.9S,15aR)-6,9-Dibenzyl-3-(6-oxo-6-((2S,3R)-3-undecyloxiran-2-yl)hexyl)octahydro-2H-pyndo[l, 2-a][l, 4, 7, 10]tetraazacyclododecine-l,4,7,10(3H,12H)-tetraone or (35',61S',91S',12R)-3,6-dibenzyl-9-[6-[(2S)-oxiran-2-yl]-6-oxohexyl]-l,4,7,10-tetrazabicyclo[10.4.0]hexadecane-2,5,8,l 1-tetrone; and one or more pharmaceutically acceptable carriers.

[0159] Disclosed herein is a pharmaceutical formulation comprising one or more disclosed compound and one or more pharmaceutically acceptable carriers.

[0160] Disclosed herein is a pharmaceutical formulation comprising one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof:Formula (I), wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3, R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon: and one or more pharmaceutically acceptable carriers.

[0161] Disclosed herein is a pharmaceutical formulation comprising one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof:GW173 (091019-869493)Formula (I); wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3, R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon: with the proviso that the compound is not (3S,6S.9S,15aR)-6,9-Dibenzyl-3-(6-oxo-6-((2S,3R)-3-undecyloxiran-2-yl)hexyl)octahydro-2H-pyndo[l, 2-a][l, 4, 7, 10]tetraazacyclododecine-l,4,7,10(3H,12H)-tetraone or (35',61S',91S',12R)-3,6-dibenzyl-9-[6-[(2S)-oxiran-2-yl]-6-oxohexyl]-l,4,7,10-tetrazabicyclo[10.4.0]hexadecane-2,5,8,l 1-tetrone; and one or more pharmaceutically acceptable carriers.

[0162] Disclosed herein is a pharmaceutical formulation comprising TD047 and one or more pharmaceutically acceptable carriers.

[0163] Disclosed herein is a pharmaceutical formulation comprising TD047 and one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof:Formula (I), wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3, R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon: and one or more pharmaceutically acceptable carriers.

[0164] Disclosed herein is a pharmaceutical formulation comprising TD047 and one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof:GW173 (091019-869493)Formula (I); wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3, R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon: with the proviso that the compound is not (3S,6S.9S,15aR)-6,9-Dibenzyl-3-(6-oxo-6-((2S,3R)-3-undecyloxiran-2-yl)hexyl)octahydro-2H-pyndo[l, 2-a][l, 4, 7, 10]tetraazacyclododecine-l,4,7,10(3H,12H)-tetraone or (35',61S',91S',12R)-3,6-dibenzyd-9-[6-[(2S)-oxiran-2-yl]-6-oxohexyl]-l,4,7,10-tetrazabicyclo[10.4.0]hexadecane-2,5,8,l 1-tetrone; and one or more pharmaceutically acceptable carriers.

[0165] In an aspect, a disclosed n can be an integer from 1 to about 6. In an aspect, a disclosed n can be 1, 2, 3, 4, or 5. In an aspect, a disclosed n can be 1. In an aspect, a disclosed n can be 2. In an aspect, a disclosed n can be 3. In an aspect, a disclosed n can be 4. In an aspect, a disclosed n can be 5. In an aspect, a disclosed n can be 6.

[0166] In an aspect, Ri can be C1-C15 alkyl or substituted alkyl. In an aspect, a substituted alkyl in Ri can be substituted with one or more halogens or one or more hydroxy. In an aspect, a disclosed halogen can be fluorine, chloride, bromine, or iodine. In an aspect, Ri can be a C3-C5 substituted cycloalkyl. In an aspect, Ri may be a cyclopropyl, a substituted cyclopropyl, a cyclobutyl, a substituted cyclobutyl, a cyclopentyl, or a substituted cyclopenyl. In an aspect, the cycloalkyl may be substituted with one or more halogens. For example, in an aspect, the cycloalkyl may be substituted with one or more of fluorine, chlorine, bromine, or iodine. In an aspect, the cycloalkyd can be substituted with a substituted Ci-Ce alkyl. In an aspect, a substituted alkyl can be substituted with one or more halogens or one or more hydroxy. For example, in an aspect, the substituted alkyl can be -CF3, -CHF2-CH2F, -CCI3, -CHC12, -CH2C1, -CBr3, -CHBr2-CH2Br -COH3, -CHOH2, or -CH2OH.

[0167] In an aspect, Ri can be C3-C5 substituted heterocyclyl. In an aspect, the heterocyclyl can be substituted with a C1-C12 alkyd or a C1-C12 substituted alkyl. In an aspect, Ri can be a substituted oxirane or a substituted 1,3-dioxolane. In an aspect, Ri can beGW173 (091019-869493)integer from 1 to 10. In an aspect, m can be 1. In an aspect, m can be 2. In an aspect, m can be 3. In an aspect, m can be 4. In an aspect, m can be 5. In an aspect, m can be 6. In an aspect, m can be 7. In an aspect, m can be 8. In an aspect, m can be 9. In an aspect, m can be 10.

[0168] In an aspect, R2 can be a hydrogen -OR?.

[0169] In an aspect, R? can be polyalkylene oxide. Polyalkylene oxide can be considered a subset of alkoxy-containing substituents. For example, in an aspect, the alkoxy-containing substituents can include ethylene oxide units. In an aspect, the polyalkylene oxide can be -(CFh-CFh-O)?-CH3. In an aspect, incorporation of a polyalkylene oxide moiety can improve one or more properties selected from aqueous solubility , metabolic stability, cellular permeability', or target engagement.

[0170] In an aspect, a disclosed compound can be any one of:GW173 (091019-869493)

[0171] In an aspect of a disclosed pharmaceutical formulation, a disclosed compound can be synthesized using standard peptide coupling, alkylation, ether formation, epoxidation, and functional group interconversion techniques known in the art. Chiral centers may be introduced using enantioselective synthesis or resolved using conventional methods. Polyalkylene oxide substituents may be introduced prior to or subsequent to macrocycle formation. Polyalkylene oxide moieties may be introduced via ether formation, nucleophilic substitution, or coupling reactions using appropriately functionalized intermediates. Protection and deprotection strategies may be employed as necessary.

[0172] In an aspect, a disclosed pharmaceutical formulation can comprise one or more diluents, binders, fdlers, buffering agents, pH modifying agents, disintegrants, dispersants, preservatives, lubricants, taste-masking agents, flavoring agents, coloring agents, or any combination thereof.

[0173] In an aspect, a disclosed pharmaceutical formulation can comprise (i) one or more active agents, (ii) biologically active agents, (iii) one or more pharmaceutically active agents, (iv) one or more immune-based therapeutic agents, (v) one or more clinically approved agents, or (vi) a combination thereof.

[0174] In an aspect, a disclosed pharmaceutical formulation can further comprise one or more anti-inflammatory agents. Anti-inflammatory agents or drugs include, but are not limited to.GW173 (091019-869493)steroids and glucocorticoids (including betamethasone, budesonide, dexamethasone, hydrocortisone acetate, hydrocortisone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone), nonsteroidal anti-inflammatory drugs (NSAIDS) including aspirin, ibuprofen, naproxen, methotrexate, sulfasalazine, leflunomide, anti-TNF medications, cyclophosphamide and my cophenolate.

[0175] In an aspect, NSAIDs can comprise ibuprofen, naproxen, naproxen sodium, Cox-2 inhibitors such as rofecoxib and celecoxib, sialylates, or any combination thereof. In an aspect, analgesics can comprise acetaminophen, oxycodone, tramadol, proporxyphene hydrochloride, or any combination thereof. In an aspect, glucocorticoids can comprise cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, or any combination thereof. Exemplary biological response modifiers include molecules directed against cell surface markers (e.g., CD4, CD5, etc.), cytokine inhibitors, such as the TNF antagonists (e.g., etanercept, adalimumab, and infliximab, chemokine inhibitors and adhesion molecule inhibitors. In an aspect, biological response modifiers can comprise monoclonal antibodies as well as recombinant forms of molecules. In an aspect, exemplary disease-modifying anti -rheumatic drugs (DMARDs) can comprise include azathioprine, cyclophosphamide, cyclosporine, methotrexate, penicillamine, leflunomide, sulfasalazine, hydroxychloroquine, Gold (oral (auranofm) and intramuscular), minocycline, or any combination thereof.

[0176] In an aspect, a disclosed chemotherapeutic agent in a disclosed pharmaceutical formulation can comprise an anthracy cline, a vinca alkaloid, an alky lating agent, an immune cell antibody, an antimetabolite, a TNFR glucocorticoid induced TNFR related protein (GITR) agonist, a proteasome inhibitor, an immunomodulator, or any combination thereof. In an aspect, a disclosed chemotherapeutic agent can comprise 5 -fluorouracil (Adrucil, Efudex), 6-mercaptopurine (Purinethol), 6-thioguanine, aclarubicin or aclacinomycin A, alemtuzamab (Lemtrada), anastrozole (Arimidex), bicalutamide (Casodex), bleomycin sulfate (Blenoxane), bortezomib (Velcade), busulfan (Myleran), busulfan injection (Busulfex), capecitabine (Xeloda), carboplatin (Paraplatin), carmustine (BiCNU), chlorambucil (Leukeran), cisplatin (Platinol), cladribine (Leustatin), Cosmegan, cyclophosphamide (Cytoxan or Neosar), cyclophosphamide, cytarabine liposome injection (DepoCyt), cytarabine, cytosine arabinoside (Cytosar-U), dacarbazine (DTIC-Dome), dactinomycin (Cosmegen), daunorubicin citrate liposome injection (DaunoXome), daunorubicin hydrochloride (Cerubidine), dexamethasone, docetaxel (Taxotere), doxorubicin hydrochloride (Adriamycin, Rubex), etoposide (Vepesid). fludarabine phosphate (Fludara), flutamide (Eulexin), folic acid antagonists, gemcitabine (difluorodeoxycitidine), gemtuzumab, gliotoxin, hydroxyurea (Hydrea), Idarubicin (Idamycin), ifosfamide (IFEX), ifosfamide,GW173 (091019-869493)irinotecan (Camptosar), L-asparaginase (ELSPAR), lenalidomide), leucovorin calcium, melphalan (Alkeran), melphalan, methotrexate (Folex), mitoxantrone (Novantrone), mylotarg, N4-pentoxycarbonyl-5 deoxy-5-fluorocytidine, nab-paclitaxel (Abraxane), paclitaxel (Taxol), pentostatin, phoenix (Yttrium90 / MX-DTPA), polifeprosan 20 with carmustine implant (Gliadel), purine analogs and adenosine deaminase inhibitors (fludarabine), pyrimidine analogs, rituximab, tamoxifen citrate (Nolvadex), temozolomide), teniposide (Vumon), tezacitibine, thalidomide or a thalidomide derivative, thiotepa, tirapazamine (Tirazone), topotecan hydrochloride for injection (Hycamptin), tositumomab), vinblastine (Velban), vinblastine, vincristine (Oncovin), vindesine, vinorelbine (Navelbine), or any combination thereof.

[0177] In an aspect, a disclosed pharmaceutical formulation can comprise an anti-chemokine therapy that enhances the resident memory T cell formations in tumor-free tissues. In an aspect, a disclosed anti-chemokine therapy can comprise one or more antibodies against CCL1, CCL2, CCL4, CCL17, CCL19, CCL21, CCL22, CCL25, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CCR2, CCR5, CCR7, CCR8, CCR9. CXCR3, CXCR4, CXCR5, CX3CL1. CX3CR1, or any combination thereof.

[0178] In an aspect, a disclosed pharmaceutical formulation can comprise a targeted therapy. In an aspect, a disclosed targeted therapy can comprise one or more monoclonal antibodies. In an aspect, a disclosed monoclonal antibody can comprise an angiogenesis inhibitor (e.g., bevacizumab). a HER-2 targeted agent (e.g.. trastuzumab, pertuzumab, etc.), an anti-CD20 monoclonal antibody (e.g., rituximab, obinutuzumab, etc.), or any combination thereof. In an aspect, a disclosed targeted therapy can comprise one or more small molecule inhibitors. In an aspect, a disclosed small molecule inhibitor can comprise a tyrosine kinase inhibitor (e.g., erlotinib, sunitinib, imatinib, dasatinib, etc.), a mTOR inhibitor (e.g., everolimus), a PARP inhibitor (e.g., olaparib). a CDK inhibitor (e.g., palbociclib. ribocichb, abermaciclib, etc.), a CD4 and / or CD6 inhibitor, or any combination thereof.

[0179] In an aspect, a disclosed targeted therapy can comprise abagovomab, abciximab, abituzumab, abrilumab, actoxumab, adalimumab, adecatumumab, aducanumab, afelimomab, afutuzumab. alacizumab pegol. alemtuzumab, alirocumab, altumomab pentetate, amatuximab, anatumomab mafenatox, anetumab ravtansine, anifrolumab, anrukinzumab, apolizumab, arcitumomab, ascrinvacumab, aselizumab, atezolizumab, atinumab, atlizumab (tocilizumab), atorolimumab, bapineuzumab, basiliximab, bavituximab, bectumomab, begelomab, belimumab, benralizumab, bertilimumab, besilesomab, bevacizumab, bezlotoxumab, biciromab, bimagrumab, bimekizumab, bivatuzumab mertansine, bhnatumomab, blosozumab, bococizumab, brentuxim abvedotin, briakinumab, brodalumab, brolucizumab, brontictuzumab, canakinumab, cantuzumabGW173 (091019-869493)mertansine, cantuzumab ravtansine, caplacizumab, capromab pendetide, carlumab, catumaxomab, cbr96-doxorubicin immunoconjugate, cedelizumab, certolizumab pegol, cetuximab, citatuzumab bogatox, cixutumumab, clazakizumab, clenoliximab, clivatuzumab tetraxetan, codrituzumab, coltuximab ravtansine, conatumumab, concizumab, crenezumab, dacetuzumab, daclizumab, dalotuzumab, dapirolizumab pegol, daratumumab, dectrekumab, demcizumab, denintuzumab mafodotin. denosumab, derlotuximab biotin, detumomab, dinutuximab, diridavumab, dorlimomab aritox, drozitumab, duligotumab, dupilumab, durvalumab, dusigitumab, ecromeximab, eculizumab, edobacomab, edrecolomab, efalizumab, efungumab, eldelumab, elgemtumab, elotuzumab, elsilimomab, emactuzumab, emibetuzumab, enavatuzumab, enfortumab vedotin. enlimomab pegol. enoblituzumab, enokizumab, enoticumab, ensituximab, epitumomab cituxetan, epratuzumab, erlizumab, ertumaxomab, etanercept, etaracizumab, etrolizumab, evinacumab, evolocumab, exbivirumab, fanolesomab, faralimomab, farletuzumab, fasinumab, felvizumab, fezakinumab, ficlatuzumab, figitumumab, firivumab, flanvotumab, fletikumab, fontolizumab, foralumab, foravirumab, fresolimumab, fulranumab, futuximab, galiximab, ganitumab, gantenerumab, gavilimomab, gemtuzumab ozogamicin, gevokizumab, girentuximab, glembatumumab vedotin, golimumab, gomiliximab, guselkumab, ibalizumab, ibritumomab tiuxetan, icrucumab, idarucizumab, igovomab, imalumab, imciromab, imgatuzumab, inclacumab, indatuximab ravtansine, indusatumab vedotin, infliximab, inolimomab. inotuzumab ozogamicin, intetumumab. ipilimumab, iratumumab, isatuximab, itolizumab, ixekizumab, keliximab, labetuzumab, lambrolizumab, lampalizumab, lebrikizumab, lemalesomab, lenzilumab, lerdelimumab, lexatumumab, libivirumab, lifastuzumab vedotin, ligelizumab, lilotomab satetraxetan, lintuzumab, lirilumab, lodelcizumab, lokivetmab, lorvotuzumab mertansine, lucatumumab, lulizumab pegol, lumiliximab, lumretuzumab, mapatumumab, margetuximab, maslimomab, matuzumab, mavrilimumab, mepolizumab, metelimumab, milatuzumab, minretumomab, mirvetuximab soravtansine, mitumomab, mogamulizumab, morolimumab, motavizumab, moxetumomab pasudotox, muromonab-cd3, nacolomab tafenatox, namilumab, naptumomab estafenatox. narnatumab, natalizumab, nebacumab, necitumumab, nemolizumab. nerelimomab, nesvacumab, nimotuzumab, nivolumab, nofetumomab merpentan, obiltoxaximab, obinutuzumab, ocaratuzumab, ocrelizumab, odulimomab, ofatumumab, olaratumab, olokizumab, omalizumab, onartuzumab, ontuxizumab, opicinumab, oportuzumab monatox, oregovomab, orticumab, otelixizumab, otlertuzumab, oxelumab, ozanezumab, ozoralizumab, pagibaximab, palivizumab, panitumumab, pankomab, panobacumab, parsatuzumab, pascolizumab, pasotuxizumab, pateclizumab, patritumab, pembrolizumab, pemtumomab, perakizumab, pertuzumab, pexelizumab, pidilizumab,GW173 (091019-869493)pinatuzumab vedotin, pintumomab. placulumab, polatuzumab vedotin, ponezumab, priliximab, pritoxaximab, pritumumab, quilizumab, racotumomab, radretumab, rafivirumab, ralpancizumab, ramucirumab, ranibizumab, raxibacumab, refanezumab, regavirumab, reslizumab, rilotumumab, rinucumab, rituximab, robatumumab, roledumab, romosozumab, rontalizumab, rovelizumab, ruplizumab, sacituzumab govitecan, samalizumab, sarilumab, satumomab pendetide, secukinumab, seribantumab, setoxaximab, sevirumab. sibrotuzumab. sifalimumab, siltuximab, simtuzumab, siplizumab, sirukumab, sofituzumab vedotin, solanezumab, solitomab, sonepcizumab, sontuzumab, stamulumab, sulesomab, suvizumab, tabalumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tanezumab, taplitumomab paptox, tarextumab, tefibazumab, telimomab aritox, tenatumomab. teneliximab, teplizumab, teprotumumab, tesidolumab, tetulomab, ticilimumab, tigatuzumab, tildrakizumab, tocilizumab, toralizumab, tosatoxumab, tositumomab, tovetumab, tralokinumab, trastuzumab, tregalizumab, tremelimumab, trevogrumab, tucotuzumab celmoleukin, tuvirumab, ublituximab, ulocuplumab, urelumab, urtoxazumab, ustekinumab, vandortuzumab vedotin. vantictumab, vanucizumab, vapaliximab, varlilumab, vatelizumab, vedolizumab, veltuzumab, vepalimomab, vesencumab, visilizumab, volociximab, vorsetuzumab mafodotin, votumumab, zalutumumab, zanolimumab, zatuximab, ziralimumab, zolimomab aritox, or any combination thereof.

[0180] In an aspect, a disclosed targeted therapy can comprise abemaciclib, ado-trastuzumab emtansine. afatinib, alectinib. alemtuzumab, alpelisib, atezolizumab. avelumab, axitinib, bevacizumab, binimetinib, blinatumomab, bosutinib, brentuximab, brigatinib, cabozantinib, carfilzomib, cemiplimab, ceritinib, cetuximab, gilteritinib, cobimetinib, copanlisib, crizotinib, dabrafenib, dacomitinib, daratumumab, dasatinib, denosumab, dinutuximab, durvalumab, duvelisib, elotuzumab. encorafenib, entrectinib, erdafitinib, erlotinib, fam-trastuzumab deruxtecan-nxki, gefitinib, gemtuzumab, ibritumomab tiuxetan, ibrutinib, imatinib, inotuzumab, ipilumumab, ivosidenib, lapatinib, larotrectinib, Lenvatinib, lorlatinib, margetuximab-cmkb, necitumumab, neratinib, nilotinib, niraparib, nivolumab, obinutuzumab, ofatumumab, olaparib, olaratumab, osimertinib, palbociclib. panitumumab, pazopanib, pembrolizumab, pertuzumab, ponatinib, ramucirumab, regorafenib, ribociclib, rituximab, rucaparib. sorafenib, sunitinib, talazoparib, tivozanib, tositumomab, trametinib, trastuzumab, tucatinib, vandetanib, vemurafenib, vismodegib, or any combination thereof.

[0181] In an aspect, a disclosed targeted therapy for oral administration can comprise abemaciclib, afatinib, alectinib, alpelisib, axitinib, binimetinib, bosutinib. brigatinib, cabozantinib, cobimetinib, crizotinib, dabrafenib, dacomitinib, dasatinib, duvelisib, encorafenib, entrectinib, erdafitinib, erlotinib, gefitinib, gilteritinib, ibrutinib, imatinib mesylate, ivosidenib, lapatinib, larotrectinib,GW173 (091019-869493)lorlatinib, lenvatinb. neratinib, nilotinib, niraparib, olaparib, osimertinib palbociclib, pazopanib, ponatinib, regorafenib, ribociclib, rucaparib, sorafenib, sunitinib malate, talazoparib, tivozanib, trametinib, vandetanib, vemurafenib, vismodegib, or any combination thereof.

[0182] In an aspect, a disclosed targeted therapy for intravenous administration can comprise ado-trastuzumab emtansine, alemtuzumab, atezolizumab, avelumab, bevacizumab, blinatumomab, brentuximab vedotin, carfilzomib, cetuximab, cemiplimab-rwlc, certinib, copanlisib, daratumumab, dinutuximab, durvalumab, elotuzumab, fam-trastuzumab deruxtecan-nxki, gemtuzumab ozogamicin, ibritumomab tiuxetan, inotuzumab ozogamicin, ipilimumab, margetuximab-cmkb, necitumumab, nivolumab, obinutuzumab. olaratumab, panitumumab, pembrolizumab, pertuzumab, ramucirumab, rituximab, tositumomab and iodine 1131 tositumomab, trastuzumab, ublituximab-xiiy, or any combination thereof.

[0183] In an aspect, a disclosed targeted therapy for subcutaneous administration can comprise denosumab, ofatumumab, or any combination thereof.

[0184] In an aspect, a disclosed pharmaceutical formulation can comprise a therapeutically effective amount of a targeted immunotherapy agent (e.g., fam-trastuzumab-deruxtecan-nxki; trastuzumab; Herceptin Hylecta (injectable Herceptin); Herceptin biosimilars (e g., Herzuma, Kanjinti, Ogivri, Ontruzant, and Trazimera); ado-trastuzumab emtansine; margetuximab-cmkb; pertuzumab, trastuzumab, and hyaluronidase-zzxf; pertuzumab; sacituzumab govitecan-hziy; or any combination thereof).

[0185] In an aspect, a disclosed pharmaceutical formulation can comprise one or more YAP1 inhibitors and / or one or more HD AC 11 inhibitors.

[0186] In an aspect, a disclosed pharmaceutical formulation can be prepared for systemic or direct administration. In an aspect, a disclosed pharmaceutical formulation can be prepared for oral administration, intravenous administration, intra-tumoral administration, intraperitoneal administration, or any combination thereof. In an aspect, a disclosed pharmaceutical formulation can be prepared for any method of administration disclosed herein. In an aspect, a disclosed pharmaceutical formulation can be prepared for administration via multiple routes either concurrently or sequentially. For example, in an aspect, a disclosed pharmaceutical formulation can be first administered intratumorally and then be administered intravenously. In an aspect, a disclosed pharmaceutical formulation can be first administered intra-tumorally and then be administered orally. A skilled clinical can determine the best route of administration for a subject at a given time.

[0187] In an aspect, a disclosed pharmaceutical formulation can comprise one or more immune modulators. In an aspect, a disclosed pharmaceutical formulation can comprise one or moreGW173 (091019-869493)proteasome inhibitors. In an aspect, a disclosed pharmaceutical formulation can comprise one or more immunosuppressives or immunosuppressive agents. In an aspect, an immunosuppressive agent can be anti-thymocyte globulin (ATG), cyclosporine (CSP), my cophenolate mofetil (MMF), or a combination thereof. In an aspect, a disclosed pharmaceutical formulation can comprise an anaplerotic agent (such as, for example, C7 compounds like triheptanoin or MCT).

[0188] In an aspect, a disclosed pharmaceutically acceptable carrier can comprise any disclosed carrier and / or any disclosed excipient.

[0189] In an aspect, a disclosed pharmaceutical formulation can treat cancer. In an aspect, a disclosed pharmaceutical formulation can slow disease progression. In an aspect, a disclosed pharmaceutical formulation can reduce tumor growth and migration. In an aspect, a disclosed pharmaceutical formulation can reduce and / or inhibit tumor cell proliferation and / or tumor cell migration. In an aspect, a disclosed pharmaceutical formulation can decrease and / or suppress tumor growth. In an aspect, a disclosed pharmaceutical formulation can decrease and / or suppress tumor growth as evidenced by a decreased volume and / or decreased tumor weight. In an aspect, a disclosed pharmaceutical formulation can protect the subject from metastasis. In an aspect, a disclosed pharmaceutical formulation can reduce the risk of developing metastasis. In an aspect, a disclosed pharmaceutical formulation can prevent or inhibit metastasis. In an aspect, a disclosed pharmaceutical formulation can comprise reducing viabi 1 i ty of one or more cancer cells.

[0190] In an aspect, a disclosed pharmaceutical formulation can (i) prolong the subject’s survivability, (ii) increase the length of time before metastasis, (iii) reduce the risk of metastases, (iv) reduce the likelihood of surgical intervention, (v) reduce the need for administration of one or more additional therapeutic agents or regimens, (vi) reduce the size of one or more tumors in the subject, (vii) eliminate and / or reduce the size of one or more tumors in the subject, (viii) reduce or eliminate the prevalence of one or more genomic aberrations, (ix) restore the normal metabolism of one or more organ systems in the subject, (x) restore one or more aspect of cellular homeostasis and / or cellular functionality' and / or metabolic dysregulation, (xi) reduce and / or inhibit aberrant angiogenesis and / or vasculogenesis in one or more tissues and / or organs of the subject, (xii) decrease and / or suppress tumor growth, (xiii) ameliorate and / or eliminate one or more symptoms associated with the subject’s cancer, (xiv) delay the onset of one or more symptoms of the subject’s cancer, (xv) decrease and / or diminish tumor cell migration, (xvi) decrease and / or diminish tumor cell proliferation, or (xvii) any combination thereof.

[0191] In an aspect, a disclosed pharmaceutical formulation can be used in a disclosed method. In an aspect, a disclosed pharmaceutical formulation can be used in a method of treating ovarian cancer, ovarian adenocarcinoma, ovarian teratocarcinoma, lung cancer, small cell lung cancerGW173 (091019-869493)(SCLC), non-small cell lung cancer (NSCLC), squamous cell lung carcinoma, adenocarcinoma, gastric cancer, breast cancer, hepatic cancer, pancreatic cancer, skin cancer, in particular basal cell carcinoma and squamous cell carcinoma, malignant melanoma, head and neck cancer, malignant pleomorphic adenoma, sarcoma, synovial sarcoma, carcinosarcoma, bile duct cancer, bladder cancer, transitional cell carcinoma, papillary carcinoma, kidney cancer, renal cell carcinoma, clear cell renal cell carcinoma, papillary renal cell carcinoma, colon cancer, small bowel cancer, small bowel adenocarcinoma, adenocarcinoma of the ileum, testicular embryonal carcinoma, placental choriocarcinoma, cervical cancer, testicular cancer, testicular seminoma, testicular teratoma, embryonic testicular cancer, uterine cancer, teratocarcinoma, embryonal carcinoma, or any combination thereof.

[0192] In an aspect, a disclosed pharmaceutical formulation can improve the life expectancy of the subject. In an aspect, a disclosed pharmaceutical formulation can improve life expectancy compared to the cancer life expectancy of an untreated subject with the identical or near identical disease condition and the identical or near identical predicted outcome. In an aspect, a disclosed pharmaceutical formulation can result in a reduction in size of a tumor. In an aspect, a disclosed pharmaceutical formulation can result in a reduction in tumor volume. In an aspect, a disclosed pharmaceutical formulation can result in a decrease in number of tumors. In an aspect, a disclosed pharmaceutical formulation can result in a decrease in number of metastatic lesions in other tissues or organs distant from the primary tumor site. In an aspect, a disclosed pharmaceutical formulation can result in an increase in survival time of a treated subject when, for example, compared to a subject not receiving treatment. In an aspect, a disclosed pharmaceutical formulation can decrease the mortality' rate of a population of treated subjects in comparison to a population not receiving treatment. In an aspect, a disclosed pharmaceutical formulation can result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. In an aspect, a disclosed pharmaceutical formulation can result in a decrease in tumor growth rate. In an aspect, a disclosed pharmaceutical formulation can improve and / or extend the survivability of the subject, can improve a subject's quality of life, can increase and / or prolong a subject’s life span, or any combination thereof. In an aspect, a disclosed pharmaceutical formulation can stimulate an effector cell mediated immune modulator response to tumor cells. In an aspect, a disclosed pharmaceutical formulation can induce a tumor reducing immune response. In an aspect, a disclosed pharmaceutical formulation can induce phagocytosis of cancer cells in the subject. In an aspect, a disclosed pharmaceutical formulation can cross-prime an antitumor T cell response. In an aspect, a disclosed method of treating cancer can induce a tumor eliminating immune response.GW173 (091019-869493)

[0193] In an aspect, a disclosed pharmaceutical formulation can prevent and / or hinder fatty acylation of YAP by HD AC 11. In an aspect, a disclosed pharmaceutical formulation can prevent and / or hinder lysine fatty acylation of KI 81 and K254 of YAP by HDAC11. In an aspect, a disclosed pharmaceutical formulation can disrupt and / or decrease the nuclear localization of YAP. In an aspect, a disclosed pharmaceutical formulation, nuclear localization of YAP can be disrupted and / or decreased. In an aspect, a disclosed pharmaceutical formulation can decrease and / or diminish expression of HDAC11 by one or more cancer cells. In an aspect, a disclosed pharmaceutical formulation can decrease and / or diminish expression of HD AC 11 by one or more cancer cells, which can correlate with improved patient survival.

[0194] In an aspect, a disclosed pharmaceutical formulation can suppress, reduce, and / or inhibit YAP. In an aspect, a disclosed pharmaceutical formulation can suppress and / or inhibit YAP-dependent transcription programs. In an aspect, a disclosed pharmaceutical formulation can suppress, reduce, and / or inhibit HDAC11 expression and / or activity. In an aspect, a disclosed pharmaceutical formulation can suppress, reduce, and / or inhibit lysine fatty acylation of YAP. In an aspect, a disclosed pharmaceutical formulation can suppress, reduce, and / or inhibit lysine fatty acylation of YAP can occur at WW domains K181 and / or K254. In an aspect, following the administering of a disclosed pharmaceutical formulation, fatty acylation at KI 81 can promote CRM 1 -mediated nuclear export. In an aspect, following the administering of a disclosed pharmaceutical formulation, fatty acylation at K254 can facilitate ubiquitination and proteasomal degradation.

[0195] In an aspect, a disclosed pharmaceutical formulation can dysregulate the expression and / or activity of YAP. In an aspect, a disclosed pharmaceutical formulation can normalize the level of YAP expression and / or YAP activity. In an aspect, a disclosed pharmaceutical formulation can cause the level of YAP expression and / or YAP activity to be that of a control cell and / or a control tissue, or can return the level of YAP expression and / or YAP activity to a control cell level and / or a control tissue level.

[0196] In an aspect, a disclosed pharmaceutical formulation can enhance YAP-CRM1 interaction. In an aspect, a disclosed pharmaceutical formulation can enhance YAP-CRM1 interaction, thereby increasing nuclear export of YAP. In an aspect, a disclosed pharmaceutical formulation can destabilize YAP. In an aspect, a disclosed pharmaceutical formulation can reduce YAP transcriptional output. In an aspect, a disclosed pharmaceutical formulation can increase ubiquitin-mediated proteasomal degradation. In an aspect, a disclosed pharmaceutical formulation can increase ubiquitin-mediated proteasomal degradation of YAP. In an aspect, a disclosed pharmaceutical formulation can increase and / or facilitate CRM1 -mediated nuclearGW173 (091019-869493)export of YAP. In an aspect, a disclosed pharmaceutical formulation can disrupt the HDAC11-YAP axis in one or more cancerous cells. In an aspect, a disclosed pharmaceutical formulation can disrupt oncogenic YAP signaling. In an aspect, a disclosed pharmaceutical formulation can treat cancer without altering global histone acetylation or global tubulin acetylation.

[0197] In an aspect, a disclosed pharmaceutical formulation can be used to treat a YAP-driven cancer in a subject. In an aspect, a disclosed pharmaceutical formulation can be used to treat a YAP-driven malignancy in a subject. In an aspect, a disclosed pharmaceutical formulation can be used to treat a cancer having a YAP-driven tumorigenic profile.

[0198] In an aspect, a disclosed pharmaceutical formulation can be used to treat a cancer characterized by HDAC11 overexpression. In an aspect, a disclosed pharmaceutical formulation can be used to treat a cancer characterized by a HD AC 11 overexpression driven malignancy in a subject. In an aspect, a disclosed pharmaceutical formulation can be used to treat a cancer having a HDAC11 overexpression driven tumorigenic profile. In an aspect, a disclosed pharmaceutical formulation can target cancer cells characterized by HD AC 11 overexpression. In an aspect, a disclosed pharmaceutical formulation can target cancer cells characterized by HD AC 11 overexpression and increased lipid flux. In an aspect, a disclosed pharmaceutical formulation can target HD AC 11 -overexpressing cancer cells. In an aspect, a disclosed pharmaceutical formulation can target HDAC11 -overexpressing cancer cells having increased lipid flux.

[0199] In an aspect, a disclosed pharmaceutical formulation can increase and / or enhance the efficacy of one or more anti -cancer therapies administered to the subject. In an aspect, a disclosed pharmaceutical formulation comprising a disclosed HDAC11 inhibitor can increase and / or enhance the efficacy of one or more anti-cancer therapies administered to the subj ect. In an aspect, a disclosed pharmaceutical formulation comprising TD047 can increase and / or enhance the efficacy of one or more anti-cancer therapies administered to the subject.

[0200] In an aspect, a disclosed pharmaceutical formulation can be used to treat multiple sclerosis, be used to slow disease progression of multiple sclerosis, alleviate and / or ameliorate one or more symptoms of multiple sclerosis, or any combination thereof. In an aspect, a disclosed pharmaceutical formulation comprising TD047 can be used to treat multiple sclerosis, be used to slow disease progression of multiple sclerosis, alleviate and / or ameliorate one or more symptoms of multiple sclerosis, or any combination thereof.

[0201] In an aspect, a disclosed pharmaceutical formulation can improve and / or ameliorate one or more symptoms associated with MS including but not limited to i) vision problems, such as double vision or optic neuritis (inflammation of the optic nerve), which causes pain with eye movement and vision loss; (ii) muscle weakness, often in the arms and legs, and muscle stiffnessGW173 (091019-869493)with painful muscle spasms; (iii) tingling, numbness, or pain in the arms, legs, trunk, or face; (iv) clumsiness, especially difficulty staying balanced when walking; (v) bladder control problems; (vi) intermittent or constant dizziness; (vii) mental or physical fatigue; (viii) mood changes such as depression or difficulty7with emotional expression or control; (ix) cognitive changes (e.g., problems concentrating, multitasking, thinking, or learning, or difficulties with memory or judgment), or (x) any combination thereof.

[0202] Tn an aspect, a disclosed pharmaceutical formulation comprising TD047 can improve and / or ameliorate one or more symptoms associated wi th MS including but not limited to i) vision problems, such as double vision or optic neuritis (inflammation of the optic nerve), which causes pain with eye movement and vision loss; (ii) muscle weakness, often in the arms and legs, and muscle stiffness with painful muscle spasms; (iii) tingling, numbness, or pain in the arms, legs, trunk, or face; (iv) clumsiness, especially difficulty7staying balanced when walking; (v) bladder control problems; (vi) intermittent or constant dizziness; (vii) mental or physical fatigue; (viii) mood changes such as depression or difficulty with emotional expression or control; (ix) cognitive changes (e.g., problems concentrating, multitasking, thinking, or learning, or difficulties with memory or judgment), or (x) any combination thereof.

[0203] In an aspect, a disclosed pharmaceutical formulation can be used to treat a neurological disease and / or disorder, be used to slow disease progression of a neurological disease and / or disorder, alleviate and / or ameliorate one or more symptoms of a neurological disease and / or disorder, or any combination thereof. In an aspect, a disclosed pharmaceutical formulation comprising TD047 can be used to treat a neurological disease and / or disorder, be used to slow disease progression of a neurological disease and / or disorder, alleviate and / or ameliorate one or more symptoms of a neurological disease and / or disorder, or any combination thereof.

[0204] In an aspect, a disclosed pharmaceutical formulation can be encapsulated in lipid nanoparticles. In an aspect, a disclosed pharmaceutical formulation comprising TD047 can be encapsulated in lipid nanoparticles.F. Methods1. Treating Cancer, Slowing Disease Progression, and / or Reducing Tumor Growth and Migration

[0205] Disclosed herein is a method of treating cancer, the method comprising administering to the subject in need thereof a therapeutically effective amount of a disclosed compound or a pharmaceutical formulation thereof.GW173 (091019-869493)

[0206] Disclosed herein is a method of treating cancer, the method comprising administering to the subject in need thereof a therapeutically effective amount of a disclosed compound of Formula (I) or a pharmaceutical formulation thereof,Formula (I), wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3, R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon, or a pharmaceutically acceptable salt thereof.

[0207] Disclosed herein is a method of treating cancer, the method comprising administering to the subject in need thereof a therapeutically effective amount of a disclosed compound of Formula (I) or a pharmaceutical formulation thereof,Formula (I); wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3, R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon; with the proviso that the compound is not (3S,6S,9S,15aR)-6,9-Dibenzyl- 3-(6-oxo-6-((2S,3R)-3-undecyloxiran-2-yl)hexyl)octahydro-2H-pyrido[l, 2-a][l, 4, 7, 10]tetraazacyclododecine-1.4,7,10(3H,12H)-tetraone or (3S,6S,9 .12.R)-3,6-dibenzyl-9-[6-[(2S)- oxiran-2-yl]-6-oxohexyl]-l,4,7,10-tetrazabicyclo[10.4.0]hexadecane-2,5,8.11-tetrone; and one or more pharmaceutically acceptable carriers.

[0208] Disclosed herein is a method of treating cancer, the method comprising administering to the subject in need thereof a therapeutically effective amount of TD047 or a pharmaceutical formulation thereof. Disclosed herein is a method of treating cancer, the method comprisingGW173 (091019-869493)administering to the subject in need thereof a therapeutically effective amount of TD047 or a pharmaceutical formulation thereof and administering one or more disclosed HDAC11 inhibitors or a pharmaceutical formulation thereof.

[0209] Disclosed herein is a method of slowing disease progression, the method comprising administering to the subject in need thereof a therapeutically effective amount of a disclosed compound or a pharmaceutical formulation thereof.

[0210] Disclosed herein is a method of slowing disease progression, the method comprising administering to the subject in need thereof a therapeutically effective amount of a disclosed compound of Formula (I) or a pharmaceutical formulation thereof,Formula (I), wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3, R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon, or a pharmaceutically acceptable salt thereof.

[0211] Disclosed herein is a method of slowing disease progression, the method comprising administering to the subject in need thereof a therapeutically effective amount of a disclosed compound of Formula (I) or a pharmaceutical formulation thereof,Formula (1); wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3, R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon; with the proviso that the compound is not (3S,6S,9S,15aR)-6,9-Dibenzyl- 3-(6-oxo-6-((2S.3R)-3-undecyloxiran-2-yl)hexyl)octahydro-2H-pyrido[l, 2-a][l. 4, 7,GW173 (091019-869493)10]tetraazacyclododecine-1.4.7.10(3H,12H)-tetraone or (3S,6<S’,9S.12A)-3.6-dibenzyl-9-[6-[(25)-oxiran-2-yl]-6-oxohexyl]-l,4,7,10-tetrazabicyclo[10.4.0]hexadecane-2,5,8,ll-tetrone; and one or more pharmaceutically acceptable carriers.

[0212] Disclosed herein is a method of slowing disease progression, the method comprising administering to the subject in need thereof a therapeutically effective amount of TD047 or a pharmaceutical formulation thereof. Disclosed herein is a method of slowing disease progression, the method comprising administering to the subject in need thereof a therapeutically effective amount of TD047 or a pharmaceutical formulation thereof and administering one or more disclosed HDAC11 inhibitors or a pharmaceutical formulation thereof.

[0213] Disclosed herein is a method of reducing tumor growth and migration, the method comprising administering to the subject in need thereof a therapeutically effective amount of a disclosed compound or a pharmaceutical formulation thereof.

[0214] Disclosed herein is a method of reducing tumor growth and migration, the method comprising administering to the subject in need thereof a therapeutically effective amount of disclosed compound of Formula (1) or a pharmaceutical formulation thereof.Formula (I), wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3, R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon, or a pharmaceutically acceptable salt thereof.

[0215] Disclosed herein is a method of reducing tumor grow th and migration, the method comprising administering to the subject in need thereof a therapeutically effective amount of disclosed compound of Formula (I) or a pharmaceutical formulation thereof,GW173 (091019-869493)Formula (I); wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3, R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon: with the proviso that the compound is not (3S,6S.9S,15aR)-6,9-Dibenzyl-3-(6-oxo-6-((2S,3R)-3-undecyloxiran-2-yl)hexyl)octahydro-2H-pyndo[l, 2-a][l, 4, 7, 10]tetraazacyclododecine-l,4,7,10(3H,12H)-tetraone or (35',61S',91S',12R)-3,6-dibenzyl-9-[6-[(2S)-oxiran-2-yl]-6-oxohexyl]-l,4,7,10-tetrazabicyclo[10.4.0]hexadecane-2,5,8,l 1-tetrone; and one or more pharmaceutically acceptable carriers.

[0216] Disclosed herein is a method of reducing tumor growth and migration, the method comprising administering to the subject in need thereof a therapeutically effective amount of TD047 or a pharmaceutical formulation thereof. Disclosed herein is a method of reducing tumor growth and migration, the method comprising administering to the subject in need thereof a therapeutically effective amount of TD047 or a pharmaceutical formulation thereof and administering one or more disclosed HD AC 11 inhibitors or a pharmaceutical formulation thereof.

[0217] In an aspect, an effective amount of TD047 can comprise about 0.5 pM to about 15 pM in cell culture. In an aspect, an effective amount of TD047 can comprise about 0.5 pM, 1.0 pM, 1.5 pM, 2.0 pM, 2.5 pM, 3.0 pM, 3.5 pM, 4.0 pM, 4.5 pM, 5.0 pM, 5.5 pM, 6.0 pM, 6.5 pM, 7.0 pM, 7.5 pM, 8.0 pM, 8.5 pM. 9.0 pM, 9.5 pM. 10.0 pM. 10.5 pM, 11.0 pM, 11.5 pM, 12.0 pM, 12.5 pM, 13.0 pM, 13.5 pM, 14.0 pM, 14.5 pM, or 15 pM in cell culture. In an aspect, an effective amount of TD047 can comprise about 10 mg / kg / day to about 40 mg / kg / day. In an aspect, an effective amount of TD047 can comprise about 10 mg / kg / day to about 20 mg / kg / day, about 20 mg / kg / day to about 30 mg / kg / day, or about 30 mg / kg / day to about 40 mg / kg / day. In an aspect, an effective amount of TD047 can comprise about 10 mg / kg / day, about 15 mg / kg / day, about 20 mg / kg / day, about 25 mg / kg / day, about 30 mg / kg / day, 35 mg / kg / day, about or about 40 mg / kg / day. In an aspect, a therapeutically effective amount can be calculated by a skilled person in the art considering the specific patient.

[0218] In an aspect, an effective amount of TD047 can comprise at least 0.5 pM to at least 15 pM in cell culture. In an aspect, an effective amount of TD047 can comprise at least 0.5 pM, 1.0 pM,GW173 (091019-869493)1.5 pM, 2.0 pM, 2.5 pM, 3.0 pM, 3.5 pM. 4.0 pM, 4.5 pM, 5.0 pM, 5.5 pM, 6.0 pM. 6.5 pM, 7.0 pM, 7.5 pM, 8.0 pM, 8.5 pM, 9.0 pM, 9.5 pM, 10.0 pM, 10.5 pM, 11.0 pM, 11.5 pM, 12.0 pM, 12.5 pM, 13.0 pM, 13.5 pM, 14.0 pM, 14.5 pM, or 15 pM in cell culture. In an aspect, an effective amount of TD047 can comprise at least 10 mg / kg / day to at least 40 mg / kg / day. In an aspect, an effective amount of TD047 can comprise at least 10 mg / kg / day to at least 20 mg / kg / day, at least 20 mg / kg / day to at least 30 mg / kg / day, or at least 30 mg / kg / day to at least 40 mg / kg / day. In an aspect, an effective amount of TD047 can comprise at least 10 mg / kg / day, at least 15 mg / kg / day, at least 20 mg / kg / day, at least 25 mg / kg / day, at least 30 mg / kg / day, 35 mg / kg / day, at least or at least 40 mg / kg / day. In an aspect, a therapeutically effective amount can be calculated by a skilled person in the art considering the specific patient.

[0219] In an aspect, a disclosed method can further comprise slowing disease progression and / or reducing tumor growth and migration. In an aspect, a disclosed method can further comprise treating cancer and / or reducing tumor growth and migration. In an aspect, a disclosed method can further comprise treating cancer and / or slowing disease progression.

[0220] In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, HD AC 11 can remove fatty acylation at both sites (i.e., WW domains KI 81 and / or K254 of YAP). In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, HD AC 11 can remove fatty acylation at both sites (i.e., WW domains K181 and / or K254 of YAP), which in turn, can sustain YAP nuclear localization and / or protein stability. In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, HDAC11 can remove fatty acylation at both sites (i.e., WW domains K181 and / or K254 ofYAP), which in turn, can sustain YAP nuclear localization and / or protein stability’ in mechanism independent of Hippo pathw ay signaling.

[0221] In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can prevent and / or hinder fatty’ acylation of YAP by HDAC11. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can prevent and / or hinder lysine fatty acylation of KI 81 and K254 ofYAP by HDAC11. In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, fatty acylation of YAP by HD AC 11 can be prevented and / or hindered. In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, lysine fatty acylation ofK181 and K254 of YAP by HDAC11 can be prevented and / or hindered.GW173 (091019-869493)

[0222] In an aspect, a disclosed method of treating cancer, slow ing disease progression, and / or reducing tumor growth and migration can disrupt and / or decrease the nuclear localization of YAP. In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor grow th and migration, nuclear localization of YAP can be disrupted and / or decreased. In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, increased expression of HD AC 11 by one or more cancer cells can correlate with poorer patient survival. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can decrease and / or diminish expression of HD AC 11 by one or more cancer cells. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can decrease and / or diminish expression of HD AC 11 by one or more cancer cells, which can correlate with improved patient survival.

[0223] In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, following the administering step, YAP expression can be suppressed, reduced, and / or inhibited. In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, YAP-dependent transcription programs can be suppressed and / or inhibited. In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, HDAC11 expression and / or activity can be suppressed, reduced, and / or inhibited. In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, the suppression, reduction, and / or inhibition of HD AC 11 in can suppress, reduce, and / or inhibit lysine fatty acylation of Y AP. In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, the suppression, reduction, and / or inhibition of lysine fatty acylation of YAP can occur at WW domains KI 81 and / or K254. In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, fatty acylation at KI 81 can promote CRM1-mediated nuclear export. In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, fatty acylation at K254 can facilitate ubiquitination and proteasomal degradation.

[0224] In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, following the administering of a disclosed compound or pharmaceutical formulation thereof, the expression and / or activity of YAP can be less dysregulated.GW173 (091019-869493)

[0225] In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, following the administering of a disclosed compound or pharmaceutical formulation thereof, the level of YAP expression and / or YAP activity can be more normalized when compared to a pre-administration level. In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, following the administering of a disclosed compound or pharmaceutical formulation thereof, the level of YAP expression and / or YAP activity can be made to be that of a control cell and / or a control tissue, or can be returned to a control cell level and / or a control tissue level.

[0226] In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, following the administering of a disclosed compound or pharmaceutical formulation thereof, tumor cell proliferation and / or tumor cell migration can be reduced and / or inhibited.

[0227] In an aspect, HD AC 11 can prevent CRMl-mediated nuclear export in YAP. In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, following the administering of a disclosed compound or pharmaceutical formulation thereof, the inhibition and / or decrease of HDAC11 can enhance YAP-CRM1 interaction. In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, following the administering of a disclosed compound or pharmaceutical formulation thereof, the inhibition and / or decrease of HD AC 11 can enhance YAP-CRM1 interaction, thereby increasing nuclear export of YAP.

[0228] In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, following the administering of a disclosed compound or pharmaceutical formulation thereof, inhibition of HD AC 11 expression and / or activity can destabilize YAP. In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, following the administering of a disclosed compound or pharmaceutical formulation thereof, inhibition of HD AC 11 expression and / or activity can reduce YAP transcriptional output. In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, following the administering of a disclosed compound or pharmaceutical formulation thereof, inhibition of HD AC 11 expression and / or activity can increase ubi quitin-mediated proteasomal degradation. In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, following the administering of a disclosed compound or pharmaceutical formulation thereof, inhibition of HD AC 11 expression and / or activity can increase ubi quitin-mediated proteasomal degradation of YAP. In an aspect of aGW173 (091019-869493)disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, following the administering of a disclosed compound or pharmaceutical formulation thereof, inhibition of HDAC11 expression and / or activity can increase and / or facilitate CRMl-mediated nuclear export of YAP. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can disrupt the HDAC11-YAP axis in one or more cancerous cells. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can disrupt oncogenic YAP signaling. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can treat cancer without altering global histone acetylation or global tubulin acetylation.

[0229] In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can decrease and / or suppress tumor growth. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can decrease and / or suppress tumor growth as evidenced by a decreased volume and / or decreased tumor weight. In an aspect, treating cancer, slowing disease progression, and / or reducing tumor growth and migration can comprise protecting the subject from metastasis. In an aspect, treating cancer, slowing disease progression, and / or reducing tumor growth and migration can comprise reducing the risk of developing metastasis. In an aspect, treating cancer, slowing disease progression, and / or reducing tumor growth and migration can comprise preventing or inhibiting metastasis. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can comprise reducing viability of one or more cancer cells. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can comprise protecting the subject from metastasis. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration of can comprise reducing the risk of developing metastasis. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can comprise preventing or inhibiting metastasis. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can comprise reducing viability of one or more cancer cells.

[0230] In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can comprise (i) prolonging the subject’s survivability, (ii) increasing the length of time before metastasis, (iii) reducing the risk of metastases, (iv) reducing the likelihood of surgical intervention, (v) reducing the need for administration of one or more additional therapeutic agents or regiments, (vi) reducing the size of one or more tumors in theGW173 (091019-869493)subject, (vii) eliminating and / or reducing the size of one or more tumors in the subject, (viii) reducing or eliminating the prevalence of one or more genomic aberrations, (ix) restoring the normal metabolism of one or more organ systems in the subject, (x) restoring one or more aspect of cellular homeostasis and / or cellular functionality' and / or metabolic dysregulation, (xi) reducing and / or inhibiting aberrant angiogenesis and / or vasculogenesis in one or more tissues and / or organs of the subject, (xii) decreasing and / or suppressing tumor growth, (xiii) ameliorating and / or eliminating one or more symptoms associated with the subject’s cancer, (xiv) delaying the onset of one or more symptoms of the subject’s cancer, (xv) decreasing and / or diminishing tumor cell migration, (xvi) decreasing and / or diminishing tumor cell proliferation, or (xvii) any combination thereof.

[0231] In an aspect of a disclosed method of treating cancer, following the administering of a disclosed compound or pharmaceutical formulation thereof, (i) the subject’s survivability can be prolonged, (ii) the length of time before metastasis can be increased, (iii) the risk of metastases can be reduced, (iv) the likelihood of surgical intervention can be reduced, (v) the need for administration of one or more additional therapeutic agents or regimens can be reduced, (vi) the size of one or more tumors in the subject can be reduced, (vii) one or more tumors in the subject can be eliminated and / or reduced in size, (viii) the prevalence of one or more genomic aberrations can be reduced or eliminated, (ix) the normal metabolism of one or more organ systems in the subject can be restored, (x) one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation can be restored, (xi) aberrant angiogenesis and / or vasculogenesis in one or more tissues and / or organs of the subj ect can be reduced and / or inhibited, (xii) tumor growth can be decreased and / or suppressed, (xiii) one or more symptoms associated with the subject’s cancer can be ameliorated and / or eliminated, (xiv) the onset of one or more symptoms of the subject’s cancer can be delayed, (xv) tumor cell migration can be decreased and / or diminished, (xvi) tumor cell proliferation can be decreased and / or diminished, or (xvii) any combination thereof.

[0232] In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, following the administering of TD047 or a pharmaceutical formulation thereof, (i) the subject’s survivability can be prolonged, (ii) the length of time before metastasis can be increased, (iii) the risk of metastases can be reduced, (iv) the likelihood of surgical intervention can be reduced, (v) the need for administration of one or more additional therapeutic agents or regimens can be reduced, (vi) the size of one or more tumors in the subject can be reduced, (vii) one or more tumors in the subject can be eliminated and / or reduced in size, (viii) the prevalence of one or more genomic aberrations can be reduced or eliminated, (ix) theGW173 (091019-869493)normal metabolism of one or more organ systems in the subject can be restored, (x) one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation can be restored, (xi) aberrant angiogenesis and / or vasculogenesis in one or more tissues and / or organs of the subject can be reduced and / or inhibited, (xii) tumor growth can be decreased and / or suppressed, (xiii) one or more symptoms associated with the subject's cancer can be ameliorated and / or eliminated, (xiv) the onset of one or more symptoms of the subject's cancer can be delayed, (xv) tumor cell migration can be decreased and / or diminished, (xvi) tumor cell proliferation can be decreased and / or diminished, or (xvii) any combination thereof.

[0233] In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, following the administering of a disclosed compound (such as, for example, TD047) or a pharmaceutical formulation thereof, tumor growth can be decreased and / or suppressed. In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, following the administering of a disclosed compound or pharmaceutical formulation thereof, tumor growth can be decreased and / or suppressed as evidenced by a decreased volume and / or decreased tumor weight. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can be used to treat a YAP-driven cancer in a subject. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can be used to treat a YAP-driven malignancy in a subject. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can be used to treat a cancer having a YAP-driven tumorigenic profile. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can be used to treat a cancer characterized by HD AC 11 overexpression. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can be used to treat a cancer characterized by a HD AC 11 overexpression driven malignancy in a subject. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can be used to treat a cancer having a HD AC 11 overexpression driven tumorigenic profile. In an aspect, a disclosed compound (such as, for example, TD047) or a pharmaceutical formulation thereof can target cancer cells characterized by HD AC 11 overexpression. In an aspect, a disclosed compound (such as, for example, TD047) or a pharmaceutical formulation thereof can target cancer cells characterized by HDAC11 overexpression and increased lipid flux. In an aspect, a disclosed compound (such as, for example, TD047) or a pharmaceutical formulation thereof can target HD AC 11 -overexpressing cancer cells. In an aspect, a disclosed compound (such as, for example, TD047) or aGW173 (091019-869493)pharmaceutical formulation thereof can target HDACll-overexpressing cancer cells having increased lipid flux.

[0234] In an aspect, the skilled person can determine an efficacious dose, an efficacious schedule, and an efficacious route of administration for a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof to treat cancer. In an aspect, the skilled person can determine an efficacious dose, an efficacious schedule, and an efficacious route of administration for a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof to treat and / or slow disease progression. In an aspect, the skilled person can determine an efficacious dose, an efficacious schedule, and an efficacious route of administration for a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof to reduce tumor growth and migration. In an aspect, the skilled person can also alter, change, or modify an aspect of an administering step to improve efficacy of a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof.

[0235] In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can comprise modifying one or more features or aspects of one or more steps of the method. In an aspect, modifying one or more steps of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can comprise modifying the administering step. In an aspect, a method can be altered by changing the amount of a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof administered to a subject, or by changing the frequency of administration of a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof to a subject, by changing the route of administration of a disclosed compound (such as, for example, TD047) or a disclosed pharmaceutical formulation thereof, by changing the duration of time a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof is administered to a subject, or by substituting for one or more of the disclosed components and / or reagents with a similar or equivalent component and / or reagent.

[0236] In an aspect, a subject can have cancer. In an aspect, a subject can be a human patient. In an aspect a subject can be any age (e.g., geriatric, adult, young adult, teenager, tween, adolescent, child, toddler, baby, or infant), can be male or female, can be any nationality, can be of any ethnicity, and / or can be of any race. In an aspect, a subject can be treatment-naive. Or, in an aspect, a subject can have had treatment. In an aspect, a subject can have a terminal cancer. In an aspect, a disclosed subject can have metastatic cancer or onco-metastatic cancer.GW173 (091019-869493)

[0237] In an aspect, disclosed cancer cells can be in a tumor. In an aspect, disclosed cancer cells can be in one or more tumors. In an aspect, disclosed cancer cells can be blood bome.

[0238] In an aspect, cancer cells can comprise ovarian cancer, ovarian adenocarcinoma, ovarian teratocarcinoma, lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous cell lung carcinoma, adenocarcinoma, gastric cancer, breast cancer, hepatic cancer, pancreatic cancer, skin cancer, in particular basal cell carcinoma and squamous cell carcinoma, malignant melanoma, head and neck cancer, malignant pleomorphic adenoma, sarcoma, synovial sarcoma, carcinosarcoma, bile duct cancer, bladder cancer, transitional cell carcinoma, papillary' carcinoma, kidney cancer, renal cell carcinoma, clear cell renal cell carcinoma, papillary renal cell carcinoma, colon cancer, small bowel cancer, small bowel adenocarcinoma, adenocarcinoma of the ileum, testicular embryonal carcinoma, placental choriocarcinoma, cervical cancer, testicular cancer, testicular seminoma, testicular teratoma, embryonic testicular cancer, uterine cancer, teratocarcinoma, embryonal carcinoma, or any combination thereof.

[0239] Thus, in an aspect, a subject can have, be diagnosed with, or be suspected of having ovarian cancer, ovarian adenocarcinoma, ovarian teratocarcinoma, lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous cell lung carcinoma, adenocarcinoma, gastric cancer, breast cancer, hepatic cancer, pancreatic cancer, skin cancer, in particular basal cell carcinoma and squamous cell carcinoma, malignant melanoma, head and neck cancer, malignant pleomorphic adenoma, sarcoma, synovial sarcoma, carcinosarcoma, bile duct cancer, bladder cancer, transitional cell carcinoma, papillary' carcinoma, kidney cancer, renal cell carcinoma, clear cell renal cell carcinoma, papillary' renal cell carcinoma, colon cancer, small bowel cancer, small bowel adenocarcinoma, adenocarcinoma of the ileum, testicular embryonal carcinoma, placental choriocarcinoma, cervical cancer, testicular cancer, testicular seminoma, testicular teratoma, embryonic testicular cancer, uterine cancer, teratocarcinoma, embryonal carcinoma, or any combination thereof. In an aspect, a subject can have ovarian cancer, colon cancer, lung cancer, or any combination.

[0240] In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can further comprise collecting one or more blood and / or biological samples from a subject at the same time or at different times. For example, in an aspect, a blood sample and / or a biological sample can be collected from a subject at a pre-determined interval. In an aspect, a pre-determined interval can be once a week, once every 2 weeks, once every' 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, or at a longer interval. In an aspect, a pre-determined interval can be once aGW173 (091019-869493)month, once every 2 months, once every 3 months, once every’ 5 months, once every 5 months, once every 6 months, or at a longer interval. In an aspect, a blood sample and / or a biological sample can be collected from a subj ect prior to treatment, during treatment, after treatment, or any combination thereof. In an aspect, a disclosed blood and / or a disclosed biological sample can be collected from a subject at any time deemed medically and / or clinically appropriate by the skilled clinician.

[0241] In an aspect, a therapeutically effective amount or effective dose or effective amount or therapeutically effective dosage of a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof can be any amount that, when used alone or in combination with another therapeutic agent, can attack and destroy one or more tumor cells and / or one or more cancer cells.

[0242] In an aspect, a therapeutically effective amount or effective dose or effective amount or therapeutically effective dosage of a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof can be any amount that, when used alone or in combination with another therapeutic agent, can protect a subject against the onset of a disease and / or promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. The ability- of a disclosed compound (such as, for example. TD047) and / or a disclosed pharmaceutical formulation thereof to promote disease regression can be evaluated using a variety of methods know n to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.

[0243] In an aspect, administering a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof can comprise systemic or direct administration. In an aspect, administering can comprise oral administration, intravenous administration, intra-tumoral administration, intraperitoneal administration, or any combination thereof. In an aspect, administering a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof can be administered by any method of administration disclosed herein. In an aspect, a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof can be administered via multiple routes either concurrently or sequentially.

[0244] For example, in an aspect, a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof can be first administered intra-tumorally and then be administered intravenously. In an aspect, a disclosed compound (such as, for example, TD047)GW173 (091019-869493)and / or a disclosed pharmaceutical formulation thereof can be first administered intra-tumorally and then be administered orally. A skilled clinician can determine the best route of administration for a subject at a given time.

[0245] In an aspect, a disclosed method of treating cancer, slow ing disease progression, and / or reducing tumor growth and migration can comprise repeating the administering of a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can further comprise obtaining a tissue biopsy from the subject. In an aspect, a disclosed tissue biopsy can be subjected to next generation sequencing. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can comprise subjecting the subject to one or more invasive or non-invasive diagnostic assessments. Diagnostic assessments are known to the art. In an aspect, a disclosed non-invasive diagnostic assessment can comprise x-rays, computerized tomography (CT) scans, magnetic resonance imaging (MRI) scans, ultrasounds, positron emission tomography (PET) scans, or any combination thereof. In an aspect, a disclosed invasive diagnostic assessment can comprise a tissue biopsy or exploratory surgery.

[0246] In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can improve the life expectancy of the subject. In an aspect, the subject's life expectancy is compared to the life expectancy of a control. In an aspect, a control is a subject not receiving a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof. In an aspect, a control is a subject not a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof. In an aspect, a control is a pooled number of subjects not receiving a disclosed compound (such as, for example. TD047) and / or a disclosed pharmaceutical formulation thereof. In an aspect, a control is one or more subjects having the same type of cancer and the same stage of cancer as the subj ect. In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration of prolonging the survival of a subject, the subject's cancer is treated.

[0247] In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can improve life expectancy compared to the cancer life expectancy of an untreated subject with the identical or near identical disease condition and the identical or near identical predicted outcome. In an aspect, “life expectancy'’ is defined as the time at which 50 percent of subjects are alive and 50 percent have passed away. In an aspect, patient life expectancy can be indefinite following treatment with a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration. In an aspect,GW173 (091019-869493)patient life expectancy can be increased at least about 5% to at least about 100%, at least about 10% to at least about 95%, at least about 20% to at least about 80%, at least about 40% to at least about 60% compared to an untreated subject with the identical or near identical disease condition and the identical or near identical predicted outcome. In an aspect, life expectancy can be increased at least about 5%. at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100% compared to an untreated subject with the identical or near identical disease condition and the identical or near identical predicted outcome. In an aspect, life expectancy can be increased at least about 5% to at least about 10%, at least about 10% to at least about 15%, at least about 15% to at least about 20%, at least about 20% to at least about 25%, at least about 25% to at least about 30%, at least about 30% to at least about 35%, at least about 35% to at least about 40%, at least about 40% to at least about 45%, at least about 45% to at least about 50%, at least about 50% to at least about 55%, at least about 55% to at least about 60%, at least about 60% to at least about 65%, at least about 65% to at least about 70%, at least about 70% to at least about 75%, at least about 75% to at least about 80%, at least about 80% to at least about 85%, at least about 85% to at least about 90%, at least about 90% to at least about 95%, at least about 95% to at least about 100% compared to an untreated patient with the identical or near identical disease condition and the identical or near identical predicted outcome.

[0248] For example, in an aspect, tumor grow th can be impaired at least about 5% to at least about 100%, at least about 10% to at least about 95%, at least about 20% to at least about 80%, at least about 40% to at least about 60% compared to an untreated subject having the identical or near identical disease condition and the identical or near identical predicted outcome. In an aspect, one or more tumors in a subject treated using a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can grow at least 5% less (or more as described above) when compared to an untreated subject with the identical or near identical disease condition and identical or near identical predicted outcome.

[0249] In an aspect, tumor grow th can be impaired at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100% compared to an untreated subject with the identical or near identical disease condition and identical or near identical predicted outcome.GW173 (091019-869493)

[0250] In an aspect, tumor growth can be impaired at least about 5% to at least about 10%, at least about 10% to at least about 15%, at least about 15% to at least about 20%, at least about 20% to at least about 25%, at least about 25% to at least about 30%, at least about 30% to at least about 35%, at least about 35% to at least about 40%, at least about 40% to at least about 45%, at least about 45% to at least about 50%, at least about 50% to at least about 55%, at least about 55% to at least about 60%, at least about 60% to at least about 65%. at least about 65% to at least about 70%, at least about 70% to at least about 75%, at least about 75% to at least about 80%, at least about 80% to at least about 85%, at least about 85% to at least about 90%, at least about 90% to at least about 95%, at least about 95% to at least about 100% compared to an untreated subject with the identical or near identical disease condition and identical or near identical predicted outcome.

[0251] In an aspect, treatment of a subject tumors according to a method disclosed herein can result in a shrinking of a tumor in comparison to the starting size of the tumor. In an aspect, tumor shrinking is at least about 5% to at least about 10%, at least about 10% to at least about 15%, at least about 15% to at least about 20%, at least about 20% to at least about 25%, at least about 25% to at least about 30%, at least about 30% to at least about 35%, at least about 35% to at least about 40%, at least about 40% to at least about 45%, at least about 45% to at least about 50%, at least about 50% to at least about 55%, at least about 55% to at least about 60%, at least about 60% to at least about 65%, at least about 65% to at least about 70%. at least about 70% to at least about 75%, at least about 75% to at least about 80%, at least about 80% to at least about 85%, at least about 85% to at least about 90%, at least about 90% to at least about 95%, at least about 95% to at least about 100% (meaning that the tumor is completely gone after treatment) compared to the starting size of the tumor.

[0252] In an aspect, a disclosed subject can present with one or more cancerous solid tumors, metastatic nodes, or any combination thereof. In any aspect, a subject herein can have a cancerous tumor cell source that can be less than about 0.2 cm3to at least about 20 cm3or greater, at least about 2 cm3to at least about 18 cm3or greater, at least about 3 cm’ to at least about 15 cm3or greater, at least about 4 cm3to at least about 12 cm3or greater, at least about 5 cm3to at least about 10 cm3or greater, or at least about 6 cm3to at least about 8 cm3or greater.

[0253] In an aspect, a disclosed method of treating cancer, slow ing disease progression, and / or reducing tumor grow th and migration can comprise a pan-tumor approach such as, for example, administering a disclosed compound (such as, for example, TD047) or a disclosed pharmaceutical formulation thereof.GW173 (091019-869493)

[0254] In an aspect, a disclosed method of treating cancer, slow ing disease progression, and / or reducing tumor growth and migration can result in a reduction in size of a tumor. In an aspect, a reduction in size of a tumor may also be referred to as “tumor regression”. In an aspect, after treatment, tumor size can be reduced by at least 5% relative to its size prior to treatment. In an aspect, tumor size can be reduced by at least 10%. at least 20%, at least 30%, at least 40%, at least 50%, at least 60%. at least 70%. or at least 80% relative to its size prior to treatment. Tumor size can be measured by any reproducible means of measurement. Tumor size can be measured as a diameter of the tumor. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can result in a reduction in tumor volume. In an aspect, after treatment, tumor volume can be reduced by at least 5% relative to the volume prior to treatment. In an aspect, tumor volume can be reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% relative to its volume prior to treatment. Tumor volume can be measured by any reproducible means of measurement.

[0255] In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can result in a decrease in number of tumors. In an aspect, after treatment, tumor number can be reduced by at least 5% relative to number prior to treatment. In an aspect, tumor number can be reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%. at least 70%, or at least 80% relative to its volume prior to treatment. Number of tumors can be measured by any reproducible means of measurement. The number of tumors can be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x).

[0256] In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can result in a decrease in number of metastatic lesions in other tissues or organs distant from the primary tumor site. In an aspect, after treatment, the number of metastatic lesions can be reduced by at least 5% relative to number prior to treatment. In an aspect, the number of metastatic lesions can be reduced by at least 10%, at least 20%, at least 30%. at least 40%. at least 50%. at least 60%. at least 70%. at least 80% relative to number prior to treatment. The number of metastatic lesions can be measured by any reproducible means of measurement. The number of metastatic lesions can be measured by counting metastatic lesions visible to the naked eye or at a specified magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x).

[0257] In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can result in an increase in survival time of a treated subject when, for example, compared to a subject not receiving treatment. In an aspect, survival team canGW173 (091019-869493)be increased at least 30 days, at least 60 days, at least 90 days, or at least 120 days. In an aspect, an increase in survival time of a population can be measured by any reproducible means. In an aspect, an increase in survival time of a population can be measured, for example, by calculating for a population the average length of survival following initiation of treatment with a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof.

[0258] In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can decrease the mortality rate of a population of treated subjects in comparison to a population not receiving treatment. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. In an aspect, the mortality rate can be decreased by at least 2%, at least 5%, at least 10%, or at least 25%. In an aspect, a decrease in the mortality rate of a population of treated subjects can be measured by any reproducible means. In an aspect, a decrease in the mortality rate of a population can be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with an active compound. In an aspect, a decrease in the mortality rate of a population can be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with an active compound.

[0259] In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can result in a decrease in tumor growth rate. In an aspect, after treatment, tumor growth rate can be reduced by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% relative to the number prior to treatment. In an aspect, tumor growth rate can be measured by any reproducible means of measurement. In an aspect, tumor growth rate can be measured according to a change in tumor diameter per unit time. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can result in a decrease in tumor regrowth. In an aspect, after treatment, tumor regrowih can be less than 5%, less than 10%, less than 20%; less than 30%, less than 40%, less than 50%. less than 60%, less than 70%, or less than 80%. In an aspect, tumor regrowth can be measured by any reproducible means of measurement. In an aspect, tumor regrowth can be measured, for example, by measuring an increase in the diameter of a tumor after a prior tumor shrinkage that follow ed treatment. In an aspect, a decrease in tumor regrowth can be indicated by failure of tumors to reoccur after treatment.

[0260] In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can comprise monitoring the subject for adverse effects. InGW173 (091019-869493)an aspect, in the absence of adverse effects, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor grow th and migration can comprise continuing to treat the subject. In an aspect, continuing to treat the subject can comprise continuing to administer a disclosed compound (such as, for example, TD047) or a disclosed pharmaceutical formulation thereof.

[0261] In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can further comprise administering to the subject an immune checkpoint inhibitor (e.g., an anti-PDl molecule). In an aspect, a disclosed anti-PDl molecule can comprise an anti-PDl antibody, an anti-PDLl antibody, or any combination thereof. In an aspect, a disclosed anti-PDl antibody can comprise a monoclonal antibody, a humanized monoclonal antibody, or a fragment thereof. In an aspect, a disclosed anti-PDl antibody can comprise a polyclonal antibody, a humanized polyclonal antibody, or a fragment thereof. In an aspect, a disclosed anti-PDl antibody can comprise any antibody or antibody fragment that specifically recognizes PD1. In an aspect, a disclosed anti-PDLl antibody can comprise a monoclonal antibody, a humanized monoclonal antibody, or a fragment thereof. In an aspect, a disclosed anti-PDLl antibody can comprise a polyclonal antibody, a humanized polyclonal antibody, or a fragment thereof. In an aspect, a disclosed anti-PDLl antibody can comprise any antibody or antibody fragment that specifically recognizes PDL1. Antibodies and methods of preparing antibodies are known in the art. Similarly, recombinant antibodies and methods of preparing recombinant antibodies are known in the art.

[0262] In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can further comprise repeating the administering of the anti-PD1 molecule. In an aspect, a disclosed anti-PDl molecule can be administered prior to, concurrent w ith, or after the administration of the interfering molecule.

[0263] In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, administering a disclosed anti-PDl molecule can comprise systemic or direct administration. In an aspect, administering a disclosed anti-PDl molecule can comprise intravenous administration, intra-tumoral administration, intraperitoneal administration, or any combination thereof. In an aspect, administering a disclosed can be administered by any method of administration disclosed herein. In an aspect, a disclosed anti-PDl molecule can be administered via multiple routes either concurrently or sequentially. For example, in an aspect, a disclosed anti-PDl molecule can be first administered intra-tumorally and then be administered intravenously. In an aspect, administering a disclosed anti-PDl molecule can be first administeredGW173 (091019-869493)intra-tumorally and then be administered orally. A skilled clinician can determine the best route of administration for a subject at a given time.

[0264] For example, in an aspect, a disclosed anti-PDl molecule can be administered about 3 months, about 2 months, or about 1 month prior to the administering of a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof. In an aspect, a disclosed anti-PDl molecule can be administered about 8 weeks, about 7 weeks, about 6 weeks, about 5 weeks, about 4 weeks, about 3 weeks, about 2 weeks, or about 1 week prior to the administering of a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof. In an aspect, a disclosed anti-PDl molecule can be administered about 30, 29. 28. 27. 26, 25, 24, 23, 22, 21, 20, 19, 18, 17. 16. 15. 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 day prior to the administering of a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof. In an aspect, a disclosed anti-PDl molecule can be administered about24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10. 9, 8, 7. 6, 5, 4. 3, 2, or 1 hours prior to the administering of a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof.

[0265] In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can comprise administering to the subject one or more additional anti-cancer therapies. Anti-cancer therapies are known to the art. In an aspect, a disclosed anti-cancer therapy can comprise endocrine therapy, radiotherapy, hormone therapy, gene therapy, thermal therapy, ultrasound therapy, or any combination thereof. In an aspect, a disclosed anti-cancer therapy can comprise one or more chemotherapeutic agents. In an aspect, a disclosed chemotherapeutic agent can comprise an anthracy cline, a vinca alkaloid, an alkylating agent, an immune cell antibody, an antimetabolite, a TNFR glucocorticoid induced TNFR related protein (G1TR) agonist, a proteasome inhibitor, an immunomodulator, or any combination thereof. In an aspect, a disclosed chemotherapeutic agent can comprise 5-fluorouracil (Adrucil, Efudex), 6-mercaptopurine (Purinethol), 6-thioguanine, aclarubicin or aclacinomycin A, alemtuzamab (Lemtrada), anastrozole (Arimidex), axitinib (Inlyta), bevacizumab (Avastin). bicalutamide (Casodex). bleomycin sulfate (Blenoxane), bortezomib (Velcade). busulfan (Myleran), busulfan injection (Busulfex), capecitabine (Xeloda), carboplatin (Paraplatin), carmustine (BiCNU), chlorambucil (Leukeran), cisplatin (Platinol), cladribine (Leustatin), Cosmegan, cyclophosphamide (Cytoxan or Neosar), cyclophosphamide, cytarabine liposome injection (DepoCyt), cytarabine, cytosine arabinoside (Cytosar-U). dacarbazine (DTIC-Dome), dactinomycin (Cosmegen), daunorubicin citrate liposome injection (DaunoXome), daunorubicin hydrochloride (Cerubidine), dexamethasone, docetaxel (Taxotere), doxorubicin hydrochlorideGW173 (091019-869493)(Adriamycin, Rubex), etoposide (Vepesid), fludarabine phosphate (Fludara), flutamide (Eulexin), folic acid antagonists, gemcitabine (difluorodeoxy citidine), gemtuzumab, gliotoxin, hydroxyurea (Hydrea), Idarubicin (Idamycin), ifosfamide (IFEX), ifosfamide, irinotecan (Camptosar), L-asparaginase (ELSPAR), lenalidomide), leucovorin calcium, melphalan (Alkeran), melphalan, methotrexate (Folex), mitoxantrone (Novantrone), mylotarg, N4-pentoxycarbonyl-5 deoxy-5-fluorocytidine. nab-paclitaxel (Abraxane), paclitaxel (Taxol), pentostatin, phoenix (Yttrium90 / MX-DTPA), polifeprosan 20 with carmustine implant (Gliadel), purine analogs and adenosine deaminase inhibitors (fludarabine), pyrimidine analogs, rituximab, tamoxifen citrate (Nolvadex), temozolomide), teniposide (Vumon), tezacitibine, thalidomide or a thalidomide derivative, thiotepa, tirapazamine (Tirazone), topotecan hydrochloride for injection (Hy camptin), tositumomab), vinblastine (Velban), vinblastine, vincristine (Oncovin), vindesine, vinorelbine (Navelbine), or any combination thereof. In an aspect, one or more disclosed additional anticancer therapies can be administered one or more times. In an aspect, one or more disclosed additional anti-cancer therapies can be administered by one or more routes of administration.

[0266] In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can further comprise administering to the subject one or more targeted therapies including, but not limited to, abemaciclib, ado-trastuzumab emtansine, afatinib, alectinib, alemtuzumab, alpelisib, atezolizumab, avelumab, axitinib, bevacizumab, binimetinib, blinatumomab, bosutinib, brentuximab, brigatinib, cabozantinib, carfilzomib, cemiplimab, ceritinib, cetuximab, gilteritinib, cobimetinib, copanlisib, crizotinib, dabrafenib, dacomitinib, daratumumab, dasatinib, denosumab, dinutuximab, durvalumab. duvelisib, elotuzumab, encorafenib, entrectinib, erdafitinib, erlotinib, fam-trastuzumab deruxtecan-nxki, gefitinib, gemtuzumab, ibritumomab tiuxetan, ibrutinib, imatinib, inotuzumab, ipilumumab, ivosidenib, lapatinib, larotrectimb, Lenvatinib, lorlatinib, margetuximab-cmkb, necitumumab, neratinib, nilotinib, niraparib, nivolumab, obinutuzumab, ofatumumab, olaparib, olaratumab, osimertinib, palbociclib, panitumumab, pazopanib, pembrolizumab, pertuzumab, ponatinib, ramucirumab, regorafenib, ribociclib, rituximab, rucaparib, sorafenib, sunitinib, talazoparib, tivozanib, tositumomab. trametinib. trastuzumab, tucatinib. vandetanib, vemurafenib, vismodegib, or any combination thereof. In an aspect, one or more of these targeted therapies can be administered one or more times. In an aspect, one or more disclosed targeted therapies can be administered by one or more routes of administration.

[0267] In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can further comprise administering to the subject one or more biosimilars. In an aspect, biosimilar can refer to a biologic product that is highly similar toGW173 (091019-869493)the reference product approved by a regulatory agency (e.g., the Federal Drug Administration (FDA) or the European Medicines Agency (EMA)) based on data from (i) analytical studies demonstrating that the biologic product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; (ii) animal studies (including the assessment of toxicity); and / or (iii) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is approved and intended to be used and for which approval is sought (e.g., that there are no clinically meaningful differences between the biologic product and the reference product in terms of the safety, purity, and potency of the product). In an aspect, the biosimilar product can be an interchangeable product as determined by a regulatory agency (e.g., the FDA).

[0268] In an aspect, a disclosed biosimilar can comprise an FDA approved biosimilar (e.g., Bkemv (eculizumab-aeeb), Yesafili (aflibercept-jbvf), Opuviz (aflibercept-yszy), Hercessi (trastuzumab-strf). Selarsdi (ustekinumab-aekn), Tyenne (tocilizumab-aazg), Jubbonti (denosumab-bbdz), Wyost (denosumab-bbdz), Simlandi (adalimumab-ryvk), Avzivi (bevacizumab-tnjn), Wezlana (ustekinumab-auub), Tofidence (tocilizumab-bavi), Tyruko (natalizumab-sztn), Yuflyma (adalimumab-aaty). Idacio (adalimumab-aacf), Vegzelma (bevacizumab-adcd), Stimufend (pegfilgrastim-fpgk), Cimerli (ranibizumab-eqm), Fylnetra (pegfilgrastim-pbbk), Alymsys (bevacizumab-maly), Releuko (filgrastim-ayow). Yusimry (adalimumab-aqvh), Rezvoglar (insulin glargine-aglr), Byooviz (ranibizumab-nuna), Semglee (insulin glargine-yfgn), Riabni (rituximab-arrx), Hulio (adalimumab-fkjp), Nyvepria (pegfilgrastim-apgf), Avsola (infliximab-axxq), Abrilada (adalimumab-afzb), Ziextenzo (pegfilgrastim-bmez), Hadlima (adalimumab-bwwd), Ruxience (rituximab-pvvr), Zirabev (bevacizumab-bvzr). Kanjinti (trastuzumab-anns), Eticovo (etanercept-ykro), Trazimera (trastuzumab-qyyp), Ontruzant (trastuzumab-dttb), Herzuma (trastuzumab-pkrb), Truxima (rituximab-abbs), Udenyca (pegfilgrastim-cbqv), Hyrimoz (adalimumab-adaz), Nivestym (filgrastim-aafi), Fulphila (pegfilgrastim-jmdb), Retacrit (epoetin alfa-epbx), Ixifi (infliximab-qbtx), Ogivri (trastuzumab-dkst), Mvasi (bevacizumab-awwb), Cyltezo (adalimumab-adbm), Renflexis (infliximab-abda), Amj evita (adalimumab-atto), Erelzi (etanercept-szzs), Inflectra (infliximab-dyyb), Zarxio (filgrastim-sndz), or any combination thereof. In an aspect, one or more of biosimilars can be administered one or more times. In an aspect, one or more disclosed biosimilars can be administered by one or more routes of administration.

[0269] In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can comprise administering to the subject an anti-GW173 (091019-869493)chemokine therapy. In an aspect, a disclosed anti-chemokine therapy can comprise one or more antibodies against CCL1, CCL2, CCL4, CCL17, CCL19, CCL21, CCL22, CCL25, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CCR2, CCR5, CCR7, CCR8, CCR9, CXCR3, CXCR4, CXCR5, CX3CL1, CX3CR1, or any combination thereof.

[0270] In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can comprise administering an oligonucleotide therapeutic agent. A disclosed oligonucleotide therapeutic agent can comprise a single-stranded or doublestranded DNA, iRNA, shRNA, siRNA, mRNA, non-coding RNA (ncRNA), an antisense molecule, miRNA, a morpholino, a peptide-nucleic acid (PNA), or an analog or conjugate thereof. In an aspect, a disclosed oligonucleotide therapeutic agent can be an ASO or an RNAi. In an aspect, a disclosed oligonucleotide therapeutic agent can comprise one or more modifications at any position applicable. In an aspect, a disclosed oligonucleotide therapeutic agent can comprise a CRISPR-based endonuclease. In an aspect, a disclosed endonuclease can be Cas9. CRISPR / Cas9 systems and methods are known to the art.

[0271] In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can further comprise preventing or inhibiting metastasis of cancer cells. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can comprise a 10%. 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any amount of decrease or reduction in the risk of and / or actual metastasis of cancer cells when compared to a control subject (such as, for example, a subject that has not received a disclosed treatment (e.g., a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof). In an aspect, preventing or inhibiting metastasis of cancer cells can comprise a 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% or any amount of decrease or reduction in the risk of and / or actual metastasis of cancer cells when compared to a control subject (such as, for example, a subject that has not received a disclosed treatment (e.g., a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof).

[0272] In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can comprise surgically resecting the tumor and / or cancer cells from the subject. In an aspect, following resecting the tumor and / or cancer cells from the subject, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can comprise continuing to administer to the subject a therapeutically effective amount of a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof and continuing to administer to the subject a therapeuticallyGW173 (091019-869493)effective amount of an anti-PDl molecule, a disclosed anti-chemokine therapy, a disclosed chemotherapeutic agent, any disclosed therapeutic agent, or any combination thereof.

[0273] In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration of can further comprise subjecting the subject to one or more invasive or non-invasive diagnostic assessments. Diagnostic assessments are known to the art. In an aspect, a disclosed non-invasive diagnostic assessment can comprise x-rays, computerized tomography (CT) scans, magnetic resonance imaging (MRI) scans, ultrasounds, positron emission tomography (PET) scans, or any combination thereof. In an aspect, a disclosed invasive diagnostic assessment can comprise a tissue biopsy (including a liquid biopsy and / or a solid tissue biopsy) or exploratory surgery’.

[0274] In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can restore one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation in a subject, such as, for example, a subject having cancer or cancerous cells. In an aspect, a disclosed interfering molecule can restore one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation in a subject having cancer. In an aspect, metabolic dysregulation can be associated with cancer or cancerous cells. In an aspect, restoring one or more aspects of cellular homeostasis and / or cellular functionality' can comprise one or more of the following: (i) correcting cell starvation in one or more cell types; (ii) normalizing aspects of the autophagy pathway (such as, for example, correcting, preventing, reducing, and / or ameliorating autophagy); (iii) improving, enhancing, restoring, and / or preserving mitochondrial functionality and / or structural integrity7; (iv) improving, enhancing, restoring, and / or preserving organelle functionality and / or structural integrity; (v) correcting enzyme dysregulation; (vi) reversing, inhibiting, preventing, stabilizing, and / or slowing the rate of progression of the multi-systemic manifestations of a cancer; (vii) reversing, inhibiting, preventing, stabilizing, and / or slowing the rate of progression of a cancer, or (viii) any combination thereof. In an aspect, restoring one or more aspects of cellular homeostasis can comprise improving, enhancing, restoring, and / or preserving one or more aspects of cellular structural and / or functional integrity. In an aspect, restoration can be a partial or incomplete restoration. In an aspect, restoration can be complete or near complete restoration such that the level of expression, activity, and / or functionality is similar to that of a wild-type or control level. In an aspect, restoring one or more aspects of cellular homeostasis and / or cellular functionality can comprise preventing or inhibiting metastasis of cancer cells in the subject.

[0275] In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, techniques to monitor, measure, and / or assess the restoringGW173 (091019-869493)one or more aspects of cellular homeostasis and / or cellular functionality can comprise qualitative (or subjective) means as well as quantitative (or objective) means. These means are known to the skilled person. For example, representative regulated variables and sensors relating to systemic homeostasis known to the skilled person.

[0276] In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can further comprise administering a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof one or more times, administering an anti-PDl molecule one or more times, administering one or more anticancer therapies one or more times, or administering any combination thereof one or more time.

[0277] In an aspect, preventing or inhibiting metastasis of cancer cells can comprise a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any amount of decrease or reduction in the risk of and / or actual metastasis of cancer cells when compared to a control subject (such as, for example, a subject that has not received a disclosed treatment (e.g., g a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof). In an aspect, preventing or inhibiting metastasis of cancer cells can comprise a 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% or any amount of decrease or reduction in the risk of and / or actual metastasis of cancer cells when compared to a control subject (such as, for example, a subject that has not received a disclosed treatment (e.g., a disclosed compound (such as. for example, TD047) and / or a disclosed pharmaceutical formulation thereof).

[0278] In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can comprise surgically resecting the tumor and / or cancer cells from the subject. In an aspect, following resecting the tumor and / or cancer cells from the subject, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can comprise continuing to administer to the subject a therapeutically effective amount of a disclosed pharmaceutical formulation. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can further comprise diagnosing the subject as have cancer or cancerous cells.

[0279] In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can improve and / or extend the survivability of the subject, can improve a subject’s quality of life, can increase and / or prolong a subject’s life span, or any combination thereof. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can stimulate an effector cell mediated immune modulator response to tumor cells. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor grow th and migration can induce a tumorGW173 (091019-869493)reducing immune response. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can induce phagocytosis of cancer cells in the subject. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can cross-prime an anti -tumor T cell response. In an aspect, a disclosed method of treating cancer, slow ing disease progression, and / or reducing tumor growth and migration can induce a tumor eliminating immune response. In an aspect, a disclosed pharmaceutical formulation can treat cancer. In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can comprise administering to the subject a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof.

[0280] In an aspect, a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration can further comprise sequencing one or more cancer cells and identifying one or more genomic aberrations in one or more genes. In an aspect, identifying one or more genomic aberrations can inform a treatment decision and / or treatment regimen and / or can influence a treatment decision and / or treatment regimen.

[0281] In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, a disclosed compound or pharmaceutical formulation thereof can increase and / or enhance the efficacy of one or more anti-cancer therapies administered to the subject. In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, a disclosed HDAC11 inhibitor or pharmaceutical formulation thereof can increase and / or enhance the efficacy of one or more anti-cancer therapies administered to the subj ect. In an aspect of a disclosed method of treating cancer, slowing disease progression, and / or reducing tumor growth and migration, TD047 or pharmaceutical formulation thereof can increase and / or enhance the efficacy of one or more anti -cancer therapies administered to the subj ect.2. Treating Multiple Sclerosis (MS)

[0282] Disclosed herein is a method of treating multiple sclerosis, the method comprising administering to the subject in need thereof a therapeutically effective amount of a disclosed compound or a pharmaceutical formulation thereof.

[0283] Disclosed herein is a method of treating multiple sclerosis, the method comprising administering to the subject in need thereof a therapeutically effective amount of a disclosed compound of Formula (I) or a pharmaceutical formulation thereof,GW173 (091019-869493)Formula (I), wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3, R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon, or a pharmaceutically acceptable salt thereof.

[0284] Disclosed herein is a method of treating multiple sclerosis, the method comprising administering to the subject in need thereof a therapeutically effective amount of a disclosed compound of Formula (I) or a pharmaceutical formulation thereof,Formula (I); wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3, Rs can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon: with the proviso that the compound is not (3S,6S,9S,15aR)-6,9-Dibenzyl-3-(6-oxo-6-((2S.3R)-3-undecyloxiran-2-yl)hexyl)octahydro-2H-pyrido[l, 2-a][l. 4, 7, 10]tetraazacyclododecine-l,4,7,10(3H,12H)-tetraone or (3S,65,9S,127?)-3,6-dibenzyl-9-[6-[(2 )-oxiran-2-yl]-6-oxohexyl]-l,4,7,10-tetrazabicyclo[10.4.0]hexadecane-2,5,8,l 1 -tetrone; and one or more pharmaceutically acceptable carriers.

[0285] Disclosed herein is a method of treating multiple sclerosis, the method comprising administering to the subject in need thereof a therapeutically effective amount of TD047 or a pharmaceutical formulation thereof. Disclosed herein is a method of treating multiple sclerosis, the method comprising administering to the subject in need thereof a therapeutically effective amount of TD047 or a pharmaceutical formulation thereof and administering one or more disclosed HDAC11 inhibitors or a pharmaceutical formulation thereof.GW173 (091019-869493)

[0286] In an aspect, a disclosed method of treating multiple sclerosis can compromise inhibiting HD AC 11.

[0287] In an aspect, HDAC11 can interact with 2’,3’-cyclic-nucleotide 3 ’-phosphodiesterase (CNP), neurochondrin (NCDN), calpain-2 (CAPN2), syntaxin binding protein 1 (STXBP1), myelin expression factor 2 (MYEF2), or any combination thereof.

[0288] In an aspect. CNP can be identified by one or more accession numbers including HGNC (2158), NCBI Gene (1267), Ensembl (ENSG00000173786), OMIM (123830), and UniProtKB / Swiss-Prot (P09543). CNP is localized to the myelin sheath in the central nervous system. In an aspect, CAPN2 can be identified by one or more accession numbers including HGNC (1479), NCBI Gene (824), Ensembl (ENS G00000162909), OMIM (114230), and UniProtKB / Swiss-Prot (Pl 7655). CAPN2 is localized in the cytosol and membrane. In an aspect, STXBP1 can be identified by one or more accession numbers including HGNC (11444), NCBI Gene (6812), Ensembl (ENSG00000136854), OMIM (602926), and UniProtKB / Swiss-Prot (P61764). STXBP1 is localized to presynaptic nerve terminals. In an aspect, MYEF2 can be identified by one or more accession numbers including HGNC (17940), NCBI Gene (50804), Ensembl (ENSG00000104177), OMIM (619395), and UniProtKB / Swiss-Prot (Q9P2K5). MYEF2 is localized to myelin in oligodendrocytes.

[0289] In an aspect of a disclosed method of treating multiple sclerosis, inhibiting HDAC11 can cause less demyelination and / or less immune infiltration into the spinal cord of the subject. In an aspect of a disclosed method of treating multiple sclerosis, inhibiting HD AC 11 can promote remyelination and repair in the spinal cord of the subject. In an aspect of a disclosed method of treating multiple sclerosis, following the administering of one or more disclosed compounds or disclosed pharmaceutical formulations thereof, the subject can have less demyelination and / or less immune infiltration into the spinal cord of the subject. In an aspect of a disclosed method of treating multiple sclerosis, following the administering of one or more disclosed compounds or disclosed pharmaceutical formulations thereof, there can be more remyelination and repair in the spinal cord of the subject.

[0290] In an aspect, NCDN can undergo lysine fatty acylation. In an aspect. NCDN can undergo lysine fatty acylation at K272. In an aspect, NCDN can undergo lysine fatty acylation by HDAC11. In an aspect, NCDN can undergo lysine fatty acylation at K272 by HDAC11. In an aspect of a disclosed method of treating MS, HD AC 11 can remove fatty acylation at K272 of NCDN. In an aspect, a disclosed method of treating MS can prevent and / or hinder fatty acylation of NCDN by HD AC 11. In an aspect, a disclosed method of treating MS can prevent and / or hinder lysine fatty acylation of K272 of NCDN by HD AC 11. In an aspect of a disclosed method ofGW173 (091019-869493)treating MS, fatty acylation of NCDN by HD AC 11 can be prevented and / or hindered. In an aspect of a disclosed method of MS, lysine fatty acylation of K272 of NCDN by HD AC 11 can be prevented and / or hindered. In an aspect of a disclosed method of treating MS, HD AC 11 can regulate the fatty acylation at K272 of NCDN, which can regulate interaction with mGluR5. In an aspect of a disclosed method of treating MS, HDAC11 can increase the interaction of NCDN and mGluR5. In an aspect, HDAC11 does not affect and / or does not alter NCDN protein levels. In an aspect, inhibition of HDAC11 in a disclosed method can target NCDN to the cellular membrane.

[0291] In an aspect, HDAC11 can be a druggable target in a subject having MS. In an aspect of a disclosed method of treating MS, a disclosed compound and / or pharmaceutical formulation thereof can decrease the expression and / or activity of HDAC11. In an aspect of a disclosed method of treating MS, a disclosed compound and / or pharmaceutical formulation thereof can decrease the expression and / or activity of HD AC 11, thereby increasing the activity and / or number of oligodendrocyte precursor cells (OPC). In an aspect of a disclosed method of treating MS, a disclosed compound and / or pharmaceutical formulation thereof can decrease the expression and / or activity of HD AC 11, thereby increasing the expression of myelin basic protein (MBP). In an aspect of a disclosed method of treating MS, a disclosed compound and / or pharmaceutical formulation thereof can decrease the expression and / or activity of HDAC11, thereby increasing the activity and / or number of oligodendrocyte precursor cells (OPC) and / or increasing the expression of myelin basic protein (MBP). In an aspect of a disclosed method of treating MS, a disclosed compound and / or pharmaceutical formulation thereof can decrease the expression and / or activity of HD AC 11, thereby increasing the number of myelinated axons.

[0292] In an aspect, the activity and / or level of OPCs following the administering of a disclosed compound or pharmaceutical formulation thereof to a subject in need thereof can be compared to a pre-administering step level, or can be compared to a control level (e.g., a level obtained from a subject not having MS), or can be compared to a pooled control level (e.g., a level obtained from a pool of subjects not having MS).

[0293] In an aspect, the skilled person can determine an efficacious dose, an efficacious schedule, and an efficacious route of administration for a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof to treat multiple sclerosis. In an aspect, the skilled person can determine an efficacious dose, an efficacious schedule, and an efficacious route of administration for a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof to treat and / or slow disease progression. In an aspect, the skilled person can determine an efficacious dose, an efficacious schedule, and anGW173 (091019-869493)efficacious route of administration for a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof to reduce demyelination. In an aspect, the skilled person can also alter, change, or modify an aspect of an administering step to improve efficacy of a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof.

[0294] In an aspect, a subject can have multiple sclerosis. In an aspect, multiple sclerosis (MS) can be relapsing / remitting MS, secondary progressive MS, progressive relapsing MS, primary progressive MS, and acute fulminant MS. In an aspect, a subject can be a human patient. In an aspect a subject can be any age (e.g., geriatric, adult, young adult, teenager, tween, adolescent, child, toddler, baby, or infant), can be male or female, can be any nationality, can be of any ethnicity, and / or can be of any race. In an aspect, a subject can be treatment-naive. Or, in an aspect, a subject can have had treatment.

[0295] In an aspect, a disclosed method of treating multiple sclerosis can comprise modifying one or more features or aspects of one or more steps of the method. In an aspect, modifying one or more steps of a disclosed method of treating multiple sclerosis can comprise modifying the administering step. In an aspect, a method can be altered by changing the amount of a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof administered to a subject, or by changing the frequency of administration of a disclosed compound (such as. for example, TD047) and / or a disclosed pharmaceutical formulation thereof to a subject, by changing the route of administration of a disclosed compound (such as, for example, TD047) or a disclosed pharmaceutical formulation thereof, by changing the duration of time a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof is administered to a subject, or by substituting for one or more of the disclosed components and / or reagents with a similar or equivalent component and / or reagent.

[0296] In an aspect, a disclosed method of treating multiple sclerosis can further comprise collecting one or more blood and / or biological samples from a subject at the same time or at different times. For example, in an aspect, a blood sample and / or a biological sample can be collected from a subject at a pre-determined interval. In an aspect, a pre-determined interval can be once a week, once every' 2 weeks, once every 3 weeks, once every' 4 weeks, once every 5 weeks, once every76 weeks, once every 7 weeks, once every78 weeks, or at a longer interval. In an aspect, a pre-determined interval can be once a month, once every 2 months, once every73 months, once every75 months, once every 5 months, once every 6 months, or at a longer interval. In an aspect, a blood sample and / or a biological sample can be collected from a subject prior to treatment, during treatment, after treatment, or any combination thereof. In an aspect, a disclosed bloodGW173 (091019-869493)and / or a disclosed biological sample can be collected from a subject at any time deemed medically and / or clinically appropriate by the skilled clinician.

[0297] In an aspect, a therapeutically effective amount or effective dose or effective amount or therapeutically effective dosage of a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof can be any amount that, when used alone or in combination with another therapeutic agent, can improve one or more aspects of a patient’s life.

[0298] Tn an aspect, a therapeutically effective amount or effective dose or effective amount or therapeutically effective dosage of a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof can be any amount that, when used alone or in combination with another therapeutic agent, can protect a subject against the onset of a disease and / or promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. The ability of a disclosed compound (such as, for example. TD047) and / or a disclosed pharmaceutical formulation thereof to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.

[0299] In an aspect, an effective amount of TD047 can comprise about 0.5 pM to about 15 pM in cell culture. In an aspect, an effective amount of TD047 can comprise about 0.5 pM, 1.0 pM, 1.5 pM, 2.0 pM, 2.5 pM, 3.0 pM, 3.5 pM, 4.0 pM, 4.5 pM, 5.0 pM, 5.5 pM, 6.0 pM, 6.5 pM, 7.0 pM, 7.5 pM, 8.0 pM, 8.5 pM, 9.0 pM, 9.5 pM, 10.0 pM, 10.5 pM, 11.0 pM, 11.5 pM, 12.0 pM, 12.5 pM, 13.0 pM, 13.5 pM, 14.0 pM, 14.5 pM, or 15 pM in cell culture. In an aspect, an effective amount of TD047 can comprise about 10 mg / kg / day to about 40 mg / kg / day. In an aspect, an effective amount of TD047 can comprise about 10 mg / kg / day to about 20 mg / kg / day, about 20 mg / kg / day to about 30 mg / kg / day, or about 30 mg / kg / day to about 40 mg / kg / day. In an aspect, an effective amount of TD047 can comprise about 10 mg / kg / day, about 15 mg / kg / day, about 20 mg / kg / day, about 25 mg / kg / day, about 30 mg / kg / day, 35 mg / kg / day, about or about 40 mg / kg / day. In an aspect, a therapeutically effective amount can be calculated by a skilled person in the art considering the specific patient.

[0300] In an aspect, an effective amount of TD047 can comprise at least 0.5 pM to at least 15 pM in cell culture. In an aspect, an effective amount of TD047 can comprise at least 0.5 pM, 1.0 pM, 1.5 pM, 2.0 pM, 2.5 pM, 3.0 pM, 3.5 pM. 4.0 pM, 4.5 pM, 5.0 pM, 5.5 pM, 6.0 pM, 6.5 pM, 7.0 pM, 7.5 pM, 8.0 pM, 8.5 pM, 9.0 pM, 9.5 pM, 10.0 pM, 10.5 pM, 11.0 pM, 11.5 pM, 12.0 pM, 12.5 pM, 13.0 pM, 13.5 pM, 14.0 pM, 14.5 pM, or 15 pM in cell culture. In an aspect, anGW173 (091019-869493)effective amount of TD047 can comprise at least 10 mg / kg / day to at least 40 mg / kg / day. In an aspect, an effective amount of TD047 can comprise at least 10 mg / kg / day to at least 20 mg / kg / day, at least 20 mg / kg / day to at least 30 mg / kg / day, or at least 30 mg / kg / day to at least 40 mg / kg / day. In an aspect, an effective amount of TD047 can comprise at least 10 mg / kg / day, at least 15 mg / kg / day, at least 20 mg / kg / day, at least 25 mg / kg / day, at least 30 mg / kg / day, 35 mg / kg / day, at least or at least 40 mg / kg / day. In an aspect, a therapeutically effective amount can be calculated by a skilled person in the art considering the specific patient.

[0301] In an aspect, administering a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof can comprise systemic or direct administration. In an aspect, administering can comprise oral administration, intravenous administration, intra-tumoral administration, intraperitoneal administration, or any combination thereof. In an aspect, administering a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof can be administered by any method of administration disclosed herein. In an aspect, a disclosed compound (such as. for example, TD047) and / or a disclosed pharmaceutical formulation thereof can be administered via multiple routes either concurrently or sequentially. A skilled clinician can determine the best route of administration for a subject at a given time.

[0302] In an aspect, a disclosed method of treating multiple sclerosis can comprise repeating the administering of a disclosed compound (such as, for example. TD047) and / or a disclosed pharmaceutical formulation thereof. In an aspect, a disclosed method of treating multiple sclerosis can further comprise obtaining a tissue biopsy from the subject. In an aspect, a disclosed tissue biopsy can be subjected to next generation sequencing. In an aspect, a disclosed method of treating multiple sclerosis can comprise subjecting the subject to one or more invasive or non-invasive diagnostic assessments. Diagnostic assessments are known to the art. In an aspect, a disclosed non-invasive diagnostic assessment can comprise x-rays, computerized tomography (CT) scans, magnetic resonance imaging (MRI) scans, ultrasounds, positron emission tomography (PET) scans, or any combination thereof. In an aspect, a disclosed invasive diagnostic assessment can comprise a tissue biopsy or exploratory surgery.

[0303] In an aspect, a disclosed method of treating multiple sclerosis can improve the life expectancy of the subject. In an aspect, the subject’s life expectancy is compared to the life expectancy of a control. In an aspect, a control is a subject not receiving a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof. In an aspect, a control is a subject not a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof. In an aspect, a control is a pooled number ofGW173 (091019-869493)subjects not receiving a disclosed compound (such as. for example. TD047) and / or a disclosed pharmaceutical formulation thereof. In an aspect, a control is one or more subjects having the same type of multiple sclerosis and the same stage of multiple sclerosis as the subject. In an aspect of a disclosed method of treating multiple sclerosis of prolonging the survival of a subject, the subject’s multiple sclerosis is treated.

[0304] In an aspect, a disclosed method of treating multiple sclerosis can improve life expectancy compared to the multiple sclerosis life expectancy of an untreated subject with the identical or near identical disease condition and the identical or near identical predicted outcome. In an aspect, “life expectancy” is defined as the time at which 50 percent of subjects are alive and 50 percent have passed away. In an aspect, patient life expectancy can be indefinite following treatment with a disclosed method of treating multiple sclerosis. In an aspect, patient life expectancy can be increased at least about 5% to at least about 100%, at least about 10% to at least about 95%, at least about 20% to at least about 80%, at least about 40% to at least about 60% compared to an untreated subject with the identical or near identical disease condition and the identical or near identical predicted outcome. In an aspect, life expectancy can be increased at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%. at least about 75%, at least about 80%, at least about 85%, at least about 90%. at least about 95%, at least about 100% compared to an untreated subject with the identical or near identical disease condition and the identical or near identical predicted outcome. In an aspect, life expectancy can be increased at least about 5% to at least about 10%, at least about 10% to at least about 15%, at least about 15% to at least about 20%, at least about 20% to at least about 25%, at least about 25% to at least about 30%, at least about 30% to at least about 35%, at least about 35% to at least about 40%, at least about 40% to at least about 45%, at least about 45% to at least about 50%, at least about 50% to at least about 55%, at least about 55% to at least about 60%, at least about 60% to at least about 65%, at least about 65% to at least about 70%, at least about 70% to at least about 75%, at least about 75% to at least about 80%, at least about 80% to at least about 85%. at least about 85% to at least about 90%, at least about 90% to at least about 95%, at least about 95% to at least about 100% compared to an untreated patient with the identical or near identical disease condition and the identical or near identical predicted outcome.

[0305] In an aspect, a disclosed method of treating multiple sclerosis can result in an increase in survival time of a treated subject when, for example, compared to a subject not receiving treatment. In an aspect, survival team can be increased at least 30 days, at least 60 days, at leastGW173 (091019-869493)90 days, or at least 120 days. In an aspect, an increase in survival time of a population can be measured by any reproducible means. In an aspect, an increase in survival time of a population can be measured, for example, by calculating for a population the average length of survival following initiation of treatment with a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof.

[0306] In an aspect, a disclosed method of treating multiple sclerosis can decrease the mortality rate of a population of treated subjects in comparison to a population not receiving treatment. In an aspect, a disclosed method of treating multiple sclerosis can result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. In an aspect, the mortality rate can be decreased by at least 2%, at least 5%, at least 10%, or at least 25%. In an aspect, a decrease in the mortality rate of a population of treated subjects can be measured by any reproducible means. In an aspect, a decrease in the mortality rate of a population can be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with an active compound. In an aspect, a decrease in the mortality rate of a population can be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with an active compound.

[0307] In an aspect, a disclosed method of treating multiple sclerosis can comprise monitoring the subject for adverse effects. In an aspect, in the absence of adverse effects, a disclosed method of treating multiple sclerosis can comprise continuing to treat the subject. In an aspect, continuing to treat the subject can comprise continuing to administer a disclosed compound (such as, for example, TD047) or a disclosed pharmaceutical formulation thereof.

[0308] In an aspect, a disclosed method of treating multiple sclerosis can improve and / or ameliorate one or more symptoms associated with MS including but not limited to i) vision problems, such as double vision or optic neuritis (inflammation of the optic nene), which causes pain with eye movement and vision loss; (ii) muscle weakness, often in the arms and legs, and muscle stiffness with painful muscle spasms; (iii) tingling, numbness, or pain in the arms, legs, trunk, or face; (iv) clumsiness, especially difficulty staying balanced when walking; (v) bladder control problems; (vi) intermittent or constant dizziness; (vii) mental or physical fatigue; (viii) mood changes such as depression or difficulty with emotional expression or control; (ix) cognitive changes (e.g., problems concentrating, multitasking, thinking, or learning, or difficulties with memory or judgment), or (x) any combination thereof.

[0309] In an aspect, a disclosed method of treating multiple sclerosis can comprise administering to the subject one or more additional anti-multiple sclerosis therapies. Anti-multiple sclerosisGW173 (091019-869493)therapies are limited but are known to the art. In an aspect, one or more disclosed additional antimultiple sclerosis therapies can be administered one or more times. In an aspect, one or more disclosed additional anti-multiple sclerosis therapies can be administered by one or more routes of administration.

[0310] In an aspect, a disclosed method of treating multiple sclerosis can comprise administering an oligonucleotide therapeutic agent. A disclosed oligonucleotide therapeutic agent can comprise a single-stranded or double-stranded DNA, iRNA, shRNA, siRNA, mRNA, non-coding RNA (ncRNA), an antisense molecule, miRNA, a morpholino, a peptide-nucleic acid (PNA), or an analog or conjugate thereof. In an aspect, a disclosed oligonucleotide therapeutic agent can be an ASO or an RNAi. In an aspect, a disclosed oligonucleotide therapeutic agent can comprise one or more modifications at any position applicable. In an aspect, a disclosed oligonucleotide therapeutic agent can comprise a CRISPR-based endonuclease. In an aspect, a disclosed endonuclease can be Cas9. CRISPR / Cas9 systems and methods are known to the art.

[0311] In an aspect, a disclosed method of treating multiple sclerosis of can further comprise subjecting the subject to one or more invasive or non-invasive diagnostic assessments. Diagnostic assessments are known to the art. In an aspect, a disclosed non-invasive diagnostic assessment can comprise x-rays, computerized tomography (CT) scans, magnetic resonance imaging (MRI) scans, ultrasounds, positron emission tomography (PET) scans, or any combination thereof. In an aspect, a disclosed invasive diagnostic assessment can comprise a tissue biopsy (including a liquid biopsy and / or a solid tissue biopsy) or exploratory surgery.

[0312] In an aspect, a disclosed method of treating multiple sclerosis can restore one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation in a subject, such as, for example, a subject having multiple sclerosis or multiple sclerosis. In an aspect, a disclosed interfering molecule can restore one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation in a subject having multiple sclerosis. In an aspect, metabolic dysregulation can be associated with multiple sclerosis or multiple sclerosis. In an aspect, restoring one or more aspects of cellular homeostasis and / or cellular functionality can comprise one or more of the following: (i) correcting cell starvation in one or more cell types; (ii) normalizing aspects of the autophagy pathway (such as, for example, correcting, preventing, reducing, and / or ameliorating autophagy); (iii) improving, enhancing, restoring, and / or preserving mitochondrial functionality and / or structural integrity; (iv) improving, enhancing, restoring, and / or preserving organelle functionality and / or structural integrity; (v) correcting enzyme dysregulation; (vi) reversing, inhibiting, preventing, stabilizing, and / or slowing the rate of progression of the multi-systemic manifestations of a multiple sclerosis;GW173 (091019-869493)(vii) reversing, inhibiting, preventing, stabilizing, and / or slowing the rate of progression of a multiple sclerosis, or (viii) any combination thereof. In an aspect, restoring one or more aspects of cellular homeostasis can comprise improving, enhancing, restoring, and / or preserving one or more aspects of cellular structural and / or functional integrity. In an aspect, restoration can be a partial or incomplete restoration. In an aspect, restoration can be complete or near complete restoration such that the level of expression, activity, and / or functionality is similar to that of a wild-type or control level. In an aspect, restoring one or more aspects of cellular homeostasis and / or cellular functionality can comprise preventing or inhibiting metastasis of multiple sclerosis cells in the subject.

[0313] In an aspect of a disclosed method of treating multiple sclerosis, techniques to monitor, measure, and / or assess the restoring one or more aspects of cellular homeostasis and / or cellular functionality can comprise qualitative (or subjective) means as well as quantitative (or objective) means. These means are known to the skilled person. For example, representative regulated variables and sensors relating to systemic homeostasis known to the skilled person.

[0314] In an aspect, a disclosed method of treating multiple sclerosis can further comprise administering a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof one or more times, administering one or more anti-multiple sclerosis therapies one or more times, or administering any combination thereof one or more times.

[0315] In an aspect, a disclosed method of treating multiple sclerosis can improve and / or extend the survivability of the subject, can improve a subject’s quality of life, can increase and / or prolong a subject’s life span, or any combination thereof. In an aspect, a disclosed pharmaceutical formulation can treat multiple sclerosis. In an aspect, a disclosed method of treating multiple sclerosis can comprise administering to the subject a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof.

[0316] In an aspect, a disclosed method of treating multiple sclerosis can further comprise sequencing one or more multiple sclerosis and identifying one or more genomic aberrations in one or more genes. In an aspect, identifying one or more genomic aberrations can inform a treatment decision and / or treatment regimen and / or can influence a treatment decision and / or treatment regimen.

[0317] In an aspect of a disclosed method of treating multiple sclerosis, a disclosed compound or pharmaceutical formulation thereof can increase and / or enhance the efficacy of one or more antimultiple sclerosis therapies administered to the subject. In an aspect of a disclosed method of treating multiple sclerosis, a disclosed HDAC11 inhibitor or pharmaceutical formulation thereof can increase and / or enhance the efficacy of one or more anti-multiple sclerosis therapiesGW173 (091019-869493)administered to the subject. In an aspect of a disclosed method of treating multiple sclerosis, TD047 or pharmaceutical formulation thereof can increase and / or enhance the efficacy of one or more anti-multiple sclerosis therapies administered to the subject.3. Treating Neurological Diseases and Disorders

[0318] Disclosed herein is a method of treating a neurological disease and / or disorder, the method comprising administering to the subject in need thereof a therapeutically effective amount of a disclosed compound or a pharmaceutical formulation thereof.

[0319] Disclosed herein is a method of treating a neurological disease and / or disorder, the method comprising administering to the subject in need thereof a therapeutically effective amount of a disclosed compound of Formula (I) or a pharmaceutical formulation thereof.Formula (I), wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3, R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon, or a pharmaceutically acceptable salt thereof.

[0320] Disclosed herein is a method of treating a neurological disease and / or disorder, the method comprising administering to the subject in need thereof a therapeutically effective amount of a disclosed compound of Formula (I) or a pharmaceutical formulation thereof,Formula (I); wherein n can be an integer from 1 to 6, Ri can be C1-C12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl, R2 can be hydrogen or -OR3, R3 can be hydrogen, polyalkylene oxide, or substituted amide, and * denotes can be a chiral carbon: with the proviso that the compound is not (3S,6S.9S,15aR)-6,9-Dibenzyl-GW173 (091019-869493)3-(6-oxo-6-((2S.3R)-3-undecyloxiran-2-yl)hexyl)octahydro-2H-pyrido[l, 2-a][l. 4, 7, 10]tetraazacyclododecine-l,4,7,10(3H,12H)-tetraone or (3S,65,9N127?)-3,6-dibenzyl-9-[6-[(2lS)-oxiran-2-yl]-6-oxohexyl]-l,4,7,10-tetrazabicyclo[10.4.0]hexadecane-2,5,8,l 1-tetrone; and one or more pharmaceutically acceptable carriers.

[0321] Disclosed herein is a method of treating a neurological disease and / or disorder, the method comprising administering to the subject in need thereof a therapeutically effective amount of TD047 or a pharmaceutical formulation thereof. Disclosed herein is a method of treating a neurological disease and / or disorder, the method comprising administering to the subject in need thereof a therapeutically effective amount of TD047 or a pharmaceutical formulation thereof and administering one or more disclosed HDAC11 inhibitors or a pharmaceutical formulation thereof.

[0322] In an aspect, a disclosed compound or pharmaceutical formulation thereof can suppress and / or diminish HD AC 11 activity and / or expression and / or function in one or more cells in the central nervous system and / or the peripheral nervous system of a subject. In an aspect, a disclosed compound or pharmaceutical formulation thereof can suppress and / or diminish HDAC11 activity and / or expression and / or function in one or more populations of cells in the central nervous system (CNS) and / or the peripheral nervous system (PNS) of a subject. In an aspect, cells or populations of cells can comprise neurons, Schwann cells, oligodendrocytes, glial cells, and any combination thereof. In an aspect, cells or populations of cells can comprise any cell or any population of cells in the subject’s CNS and / or PNS that shows HD AC 11 overexpression or overactivity. In an aspect, cells or populations of cells can comprise any cell or any population of cells in the subject’s CNS and / or PNS in which a decrease of HD AC 11 expression or activity’ or function by a disclosed compound or pharmaceutical formulation can be beneficial to treating the neurological disease or disorder.

[0323] In an aspect, TD047 can suppress and / or diminish HD AC 11 activity and / or expression and / or function in one or more cells in the central nervous system and / or the peripheral nervous system of a subject. In an aspect, TD047 can suppress and / or diminish HDAC11 activity7and / or expression and / or function in one or more populations of cells in the central nervous system (CNS) and / or the peripheral nervous system (PNS) of a subject. In an aspect, cells or populations of cells can comprise neurons, Schwann cells, oligodendrocytes, glial cells, and any combination thereof. In an aspect, cells or populations of cells can comprise any cell or any population of cells in the subject’s CNS and / or PNS that shows HDAC11 overexpression or overactivity. In an aspect, cells or populations of cells can comprise any cell or any population of cells in the subject's CNS and / or PNS in which a decrease of HD AC 11 expression or activity or function by TD047 can be beneficial to treating the neurological disease or disorder.GW173 (091019-869493)

[0324] In an aspect, a disclosed neurological disease or neurological disorder can be used interchangeably and refer to a host of undesirable conditions affecting cells or populations of cells in the brain of a subject. In an aspect, a disclosed neurological disease or neurological disorder can be used interchangeably and refer to a host of undesirable conditions affecting cells or populations of cells in the brain of a subject. These diseases include but are not limited to the following: Alzheimer’s disease. Parkinson’s disease, Huntington’s disease, Pick’s disease, Kufs disease, Lewy body disease, neurofibrillary tangles, Rosenthal fibers, Mallory’s hyaline, senile dementia, myasthenia gravis, Gilles de la Tourette’s syndrome, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), epilepsy, Creutzfeldt-Jakob disease, deafness-dytonia syndrome. Leigh syndrome, Leber hereditary’ optic neuropathy (LHON), parkinsonism, dystonia, motor neuron disease, neuropathy-ataxia and retinitis pimentosa (NARP), maternal inherited Leigh syndrome (MILS), Friedreich ataxia, hereditary' spastic paraplegia, Mohr-Tranebjaerg syndrome, Wilson disease, sporatic Alzheimer’s disease, sporadic amyotrophic lateral sclerosis, sporadic Parkinson’s disease, autonomic function disorders, hypertension, sleep disorders, neuropsychiatric disorders, depression, schizophrenia, schizoaffective disorder, korsakoffs psychosis, mania, anxiety disorders, phobic disorder, learning or memory' disorders, amnesia or age-related memory' loss, attention deficit disorder, dysthymic disorder, major depressive disorder, obsessive-compulsive disorder, psychoactive substance use disorders, panic disorder, bipolar affective disorder, severe bipolar affective (mood) disorder (BP-1), migraines, hyperactivity and movement disorders.

[0325] In an aspect, a disclosed neurological disease or disorder can involve neuroinflammation and / or demyelination. In an aspect, a disclosed neurological disease or disorder comprising neuroinflammation and / or demyelination that can benefit from introduction of an HD AC 11 inhibitor can include Alzheimer's Disease (AD), Huntington's Disease (HD), neuropathic pain, neuroinflammation-induced depression, traumatic brain injury (TBI), stroke, other demyelinating diseases, Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), or any combination thereof.

[0326] In an aspect, one or more proteins associated with the pathology of one or more neurological diseases or disorders can be affected by inhibition of HD AC 11 by one or more disclosed compositions or disclosed pharmaceutical formulations. In an aspect, one or more proteins associated with the pathology of one or more neurological diseases or disorders can be affected by inhibition of HD AC 11 by one or more disclosed compositions comprising one or more disclosed HDAC11 inhibitors or disclosed pharmaceutical formulations comprising one or more HDAC11 inhibitors. In an aspect, one or more proteins associated with the pathology of one orGW173 (091019-869493)more neurological diseases or disorders can be affected by inhibition of HD AC 11 by one or more disclosed compositions comprising TD047 or disclosed pharmaceutical formulations comprising one or TD047.

[0327] In an aspect, a disclosed method of treating a neurological disease and / or disorder can comprise inhibiting HD AC 11.

[0328] In an aspect, HDAC11 can interact with 2’,3’-cyclic-nucleotide 3 ’-phosphodiesterase (CNP), neurochondrin (NCDN), calpain-2 (CAPN2), syntaxin binding protein 1 (STXBP1), myelin expression factor 2 (MYEF2), or any combination thereof.

[0329] In an aspect, CNP can be identified by one or more accession numbers including HGNC (2158), NCBI Gene (1267), Ensembl (ENSG00000173786), OMIM (123830), and UniProtKB / Swiss-Prot (P09543). CNP is localized to the myelin sheath in the central nervous system. In an aspect, CAPN2 can be identified by one or more accession numbers including HGNC (1479), NCBI Gene (824), Ensembl (ENS GOOOOO 162909), OMIM (114230), and UniProtKB / Swiss-Prot (Pl 7655). CAPN2 is localized in the cytosol and membrane. In an aspect, STXBP1 can be identified by one or more accession numbers including HGNC (11444), NCBI Gene (6812), Ensembl (ENSG00000136854), OMIM (602926), and UniProtKB / Swiss-Prot (P61764). STXBP1 is localized to presynaptic nerve terminals. In an aspect, MYEF2 can be identified by one or more accession numbers including HGNC (17940), NCBI Gene (50804), Ensembl (ENS GOOOOO 104177), OMIM (619395), and UniProtKB / Swiss-Prot (Q9P2K5). MYEF2 is localized to myelin in oligodendrocytes.

[0330] In an aspect of a disclosed method of treating a neurological disease and / or disorder, inhibiting HD AC 11 can cause less demyelination and / or less immune infiltration into the spinal cord of the subject. In an aspect of a disclosed method of treating a neurological disease and / or disorder, inhibiting HDAC11 can promote remyelination and repair in the spinal cord of the subject. In an aspect of a disclosed method of treating a neurological disease and / or disorder, following the administering of one or more disclosed compounds or disclosed pharmaceutical formulations thereof, the subject can have less demyelination and / or less immune infiltration into the spinal cord of the subject. In an aspect of a disclosed method of treating a neurological disease and / or disorder, following the administering of one or more disclosed compounds or disclosed pharmaceutical formulations thereof, there can be more remyelination and repair in the spinal cord of the subject.

[0331] In an aspect, NCDN can undergo lysine fatty acylation. In an aspect, NCDN can undergo lysine fatty acylation at K272. In an aspect, NCDN can undergo lysine fatty acylation by HDAC11. In an aspect, NCDN can undergo lysine fatty acylation at K272 by HDAC11. In anGW173 (091019-869493)aspect of a disclosed method of treating a neurological disease and / or disorder, HDAC11 can remove fatty acylation at K272 of NCDN. In an aspect, a disclosed method of treating a neurological disease and / or disorder can prevent and / or hinder fatty acylation of NCDN by HDAC11. In an aspect, a disclosed method of treating a neurological disease and / or disorder can prevent and / or hinder lysine fatty acylation of K272 of NCDN by HDAC11. In an aspect of a disclosed method of treating a neurological disease and / or disorder, lath' acylation of NCDN by HDAC11 can be prevented and / or hindered. In an aspect of a disclosed method of MS, lysine fatty acylation of K272 of NCDN by HD AC 11 can be prevented and / or hindered. In an aspect of a disclosed method of treating a neurological disease and / or disorder, HD AC 11 can regulate the fatty acylation at K272 of NCDN. which can regulate interaction with mGluR5. In an aspect of a disclosed method of treating a neurological disease and / or disorder, HDAC11 can increase the interaction of NCDN and mGluR5. In an aspect, HDAC11 does not affect and / or does not alter NCDN protein levels. In an aspect, inhibition of HD AC 11 in a disclosed method can target NCDN to the cellular membrane.

[0332] In an aspect, HDAC11 can be a druggable target in a subject having MS. In an aspect of a disclosed method of treating a neurological disease and / or disorder, a disclosed compound and / or pharmaceutical formulation thereof can decrease the expression and / or activity of HDAC11. In an aspect of a disclosed method of treating a neurological disease and / or disorder, a disclosed compound and / or pharmaceutical formulation thereof can decrease the expression and / or activity of HDAC11, thereby increasing the activity and / or number of oligodendrocyte precursor cells (OPC). In an aspect of a disclosed method of treating a neurological disease and / or disorder, a disclosed compound and / or pharmaceutical formulation thereof can decrease the expression and / or activity of HD AC 11, thereby increasing the expression of myelin basic protein (MBP). In an aspect of a disclosed method of treating a neurological disease and / or disorder, a disclosed compound and / or pharmaceutical formulation thereof can decrease the expression and / or activity of HDAC11, thereby increasing the activity and / or number of oligodendrocyte precursor cells (OPC) and / or increasing the expression of myelin basic protein (MBP). In an aspect of a disclosed method of treating a neurological disease and / or disorder, a disclosed compound and / or pharmaceutical formulation thereof can decrease the expression and / or activity of HD AC 11, thereby increasing the number of myelinated axons.

[0333] In an aspect, the activity and / or level of OPCs following the administering of a disclosed compound or pharmaceutical formulation thereof to a subject in need thereof can be compared to a pre-administering step level, or can be compared to a control level (e.g., a level obtained from aGW173 (091019-869493)subject not having MS), or can be compared to a pooled control level (e.g., a level obtained from a pool of subjects not having MS).

[0334] In an aspect, the skilled person can determine an efficacious dose, an efficacious schedule, and an efficacious route of administration for a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof to treat a neurological disease and / or disorder. In an aspect, the skilled person can determine an efficacious dose, an efficacious schedule, and an efficacious route of administration for a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof to treat and / or slow disease progression. In an aspect, the skilled person can determine an efficacious dose, an efficacious schedule, and an efficacious route of administration for a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof to reduce demyelination. In an aspect, the skilled person can also alter, change, or modify an aspect of an administering step to improve efficacy of a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof.

[0335] In an aspect, a subject can have a neurological disease and / or disorder. In an aspect, a subject can be a human patient. In an aspect a subject can be any age (e g., geriatric, adult, young adult, teenager, tween, adolescent, child, toddler, baby, or infant), can be male or female, can be any nationality, can be of any ethnicity, and / or can be of any race. In an aspect, a subject can be treatment-naive. Or, in an aspect, a subject can have had treatment.

[0336] In an aspect, a disclosed method of treating a neurological disease and / or disorder can comprise modifying one or more features or aspects of one or more steps of the method. In an aspect, modifying one or more steps of a disclosed method of treating a neurological disease and / or disorder can comprise modifying the administering step. In an aspect, a method can be altered by changing the amount of a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof administered to a subject, or by changing the frequency of administration of a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof to a subject, by changing the route of administration of a disclosed compound (such as, for example, TD047) or a disclosed pharmaceutical formulation thereof, by changing the duration of time a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof is administered to a subject, or by substituting for one or more of the disclosed components and / or reagents with a similar or equivalent component and / or reagent.

[0337] In an aspect, a disclosed method of treating a neurological disease and / or disorder can further comprise collecting one or more blood and / or biological samples from a subject at theGW173 (091019-869493)same time or at different times. For example, in an aspect, a blood sample and / or a biological sample can be collected from a subj ect at a pre-determined interval. In an aspect, a pre-determined interval can be once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every' 7 weeks, once every' 8 weeks, or at a longer interval. In an aspect, a pre-determined interval can be once a month, once every 2 months, once every 3 months, once every 5 months, once everv 5 months, once every 6 months, or at a longer interval. In an aspect, a blood sample and / or a biological sample can be collected from a subject prior to treatment, during treatment, after treatment, or any combination thereof. In an aspect, a disclosed blood and / or a disclosed biological sample can be collected from a subject at any time deemed medically and / or clinically appropriate by the skilled clinician.

[0338] In an aspect, a therapeutically effective amount or effective dose or effective amount or therapeutically effective dosage of a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof can be any amount that, when used alone or in combination with another therapeutic agent, can improve one or more aspects of a patient's life.

[0339] In an aspect, a therapeutically effective amount or effective dose or effective amount or therapeutically effective dosage of a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof can be any amount that, when used alone or in combination with another therapeutic agent, can protect a subject against the onset of a disease and / or promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. The ability of a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical tnals, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.

[0340] In an aspect, an effective amount of TD047 can comprise about 0.5 pM to about 15 pM in cell culture. In an aspect, an effective amount of TD047 can comprise about 0.5 pM, 1.0 pM, 1.5 pM, 2.0 pM, 2.5 pM, 3.0 pM, 3.5 pM. 4.0 pM, 4.5 pM, 5.0 pM, 5.5 pM, 6.0 pM. 6.5 pM, 7.0 pM, 7.5 pM, 8.0 pM, 8.5 pM, 9.0 pM, 9.5 pM, 10.0 pM, 10.5 pM, 11.0 pM, 11.5 pM, 12.0 pM, 12.5 pM, 13.0 pM, 13.5 pM, 14.0 pM, 14.5 pM, or 15 pM in cell culture. In an aspect, an effective amount of TD047 can comprise about 10 mg / kg / day to about 40 mg / kg / day. In an aspect, an effective amount of TD047 can comprise about 10 mg / kg / day to about 20 mg / kg / day, about 20 mg / kg / day to about 30 mg / kg / day, or about 30 mg / kg / day to about 40 mg / kg / day. In an aspect, an effective amount of TD047 can comprise about 10 mg / kg / day, about 15 mg / kg / day, about 20GW173 (091019-869493)mg / kg / day, about 25 mg / kg / day. about 30 mg / kg / day, 35 mg / kg / day, about or about 40 mg / kg / day. In an aspect, a therapeutically effective amount can be calculated by a skilled person in the art considering the specific patient.

[0341] In an aspect, an effective amount of TD047 can comprise at least 0.5 pM to at least 15 pM in cell culture. In an aspect, an effective amount of TD047 can comprise at least 0.5 pM. 1.0 pM, 1.5 pM, 2.0 pM, 2.5 pM. 3.0 pM, 3.5 pM. 4.0 pM, 4.5 pM, 5.0 pM, 5.5 pM, 6.0 pM. 6.5 pM, 7.0 pM, 7.5 pM, 8.0 pM, 8.5 pM, 9.0 pM, 9.5 pM, 10.0 pM, 10.5 pM, 11.0 pM, 11.5 pM, 12.0 pM, 12.5 pM, 13.0 pM, 13.5 pM, 14.0 pM, 14.5 pM, or 15 pM in cell culture. In an aspect, an effective amount of TD047 can comprise at least 10 mg / kg / day to at least 40 mg / kg / day. In an aspect, an effective amount of TD047 can comprise at least 10 mg / kg / day to at least 20 mg / kg / day, at least 20 mg / kg / day to at least 30 mg / kg / day, or at least 30 mg / kg / day to at least 40 mg / kg / day. In an aspect, an effective amount of TD047 can comprise at least 10 mg / kg / day, at least 15 mg / kg / day, at least 20 mg / kg / day, at least 25 mg / kg / day, at least 30 mg / kg / day, 35 mg / kg / day, at least or at least 40 mg / kg / day. In an aspect, a therapeutically effective amount can be calculated by a skilled person in the art considering the specific patient.

[0342] In an aspect, administering a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof can comprise systemic or direct administration. In an aspect, administering can comprise oral administration, intravenous administration, intra-tumoral administration, intraperitoneal administration, or any combination thereof. In an aspect, administering a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof can be administered by any method of administration disclosed herein. In an aspect, a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof can be administered via multiple routes either concurrently or sequentially. A skilled clinician can determine the best route of administration for a subject at a given time.

[0343] In an aspect, a disclosed method of treating a neurological disease and / or disorder can comprise repeating the administering of a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof. In an aspect, a disclosed method of treating aneurological disease and / or disorder can further comprise obtaining atissue biopsy from the subject. In an aspect, a disclosed tissue biopsy can be subjected to next generation sequencing. In an aspect, a disclosed method of treating a neurological disease and / or disorder can comprise subjecting the subject to one or more invasive or non-invasive diagnostic assessments. Diagnostic assessments are known to the art. In an aspect, a disclosed non-invasive diagnostic assessment can comprise x-rays, computerized tomography (CT) scans, magnetic resonance imaging (MRI)GW173 (091019-869493)scans, ultrasounds, positron emission tomography (PET) scans, or any combination thereof. In an aspect, a disclosed invasive diagnostic assessment can comprise a tissue biopsy or exploratory surgery.

[0344] In an aspect, a disclosed method of treating a neurological disease and / or disorder can improve the life expectancy of the subject. In an aspect, the subject’s life expectancy is compared to the life expectancy of a control. In an aspect, a control is a subject not receiving a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof. In an aspect, a control is a subject not a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof. In an aspect, a control is a pooled number of subjects not receiving a disclosed compound (such as. for example. TD047) and / or a disclosed pharmaceutical formulation thereof. In an aspect, a control is one or more subjects having the same type of neurological disease and / or disorder and the same stage of neurological disease and / or disorder as the subj ect. In an aspect of a disclosed method of treating a neurological disease and / or disorder of prolonging the survival of a subject, the subject’s neurological disease and / or disorder is treated.

[0345] In an aspect, a disclosed method of treating a neurological disease and / or disorder can improve life expectancy compared to the neurological disease and / or disorder life expectancy of an untreated subject with the identical or near identical disease condition and the identical or near identical predicted outcome. In an aspect, “life expectancy” is defined as the time at which 50 percent of subjects are alive and 50 percent have passed away. In an aspect, patient life expectancy can be indefinite following treatment with a disclosed method of treating a neurological disease and / or disorder. In an aspect, patient life expectancy can be increased at least about 5% to at least about 100%, at least about 10% to at least about 95%. at least about 20% to at least about 80%, at least about 40% to at least about 60% compared to an untreated subject with the identical or near identical disease condition and the identical or near identical predicted outcome. In an aspect, life expectancy can be increased at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100% compared to an untreated subject with the identical or near identical disease condition and the identical or near identical predicted outcome. In an aspect, life expectancy can be increased at least about 5% to at least about 10%, at least about 10% to at least about 15%, at least about 15% to at least about 20%, at least about 20% to at least about 25%, at least about 25% to at least about 30%, at least about 30% to at least about 35%, at least about 35%GW173 (091019-869493)to at least about 40%, at least about 40% to at least about 45%, at least about 45% to at least about 50%, at least about 50% to at least about 55%, at least about 55% to at least about 60%, at least about 60% to at least about 65%, at least about 65% to at least about 70%, at least about 70% to at least about 75%, at least about 75% to at least about 80%, at least about 80% to at least about 85%, at least about 85% to at least about 90%, at least about 90% to at least about 95%, at least about 95% to at least about 100% compared to an untreated patient with the identical or near identical disease condition and the identical or near identical predicted outcome.

[0346] In an aspect, a disclosed method of treating a neurological disease and / or disorder can result in an increase in survival time of a treated subject when, for example, compared to a subject not receiving treatment. In an aspect, survival team can be increased at least 30 days, at least 60 days, at least 90 days, or at least 120 days. In an aspect, an increase in survival time of a population can be measured by any reproducible means. In an aspect, an increase in survival time of a population can be measured, for example, by calculating for a population the average length of survival following initiation of treatment with a disclosed compound (such as, for example, TD047) and / or a disclosed pharmaceutical formulation thereof.

[0347] In an aspect, a disclosed method of treating a neurological disease and / or disorder can decrease the mortality rate of a population of treated subjects in comparison to a population not receiving treatment. In an aspect, a disclosed method of treating a neurological disease and / or disorder can result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. In an aspect, the mortality rate can be decreased by at least 2%, at least 5%, at least 10%, or at least 25%. In an aspect, a decrease in the mortality rate of a population of treated subjects can be measured by any reproducible means. In an aspect, a decrease in the mortality rate of a population can be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with an active compound. In an aspect, a decrease in the mortality' rate of a population can be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with an active compound.

[0348] In an aspect, a disclosed method of treating a neurological disease and / or disorder can comprise monitoring the subject for adverse effects. In an aspect, in the absence of adverse effects, a disclosed method of treating a neurological disease and / or disorder can comprise continuing to treat the subject. In an aspect, continuing to treat the subject can comprise continuing to administer a disclosed compound (such as, for example, TD047) or a disclosed pharmaceutical formulation thereof.GW173 (091019-869493)

[0349] In an aspect, a disclosed method of treating a neurological disease and / or disorder can improve and / or ameliorate one or more symptoms associated with MS including but not limited to (i) vision problems, such as double vision or optic neuritis (inflammation of the optic nerve), which causes pain with eye movement and vision loss; (ii) muscle weakness, often in the arms and legs, and muscle stiffness with painful muscle spasms; (iii) tingling, numbness, or pain in the arms, legs, trunk, or face; (iv) clumsiness, especially difficulty staying balanced when walking; (v) bladder control problems; (vi) intermittent or constant dizziness; (vii) mental or physical fatigue; (viii) mood changes such as depression or difficulty with emotional expression or control; (ix) cognitive changes (e.g., problems concentrating, multitasking, thinking, or learning, or difficulties with memory’ or judgment), or (x) any combination thereof.

[0350] In an aspect, a disclosed method of treating a neurological disease and / or disorder can improve function and / or wellness in one or more following systems: visual / ocular system, musculoskeletal system, peripheral and central sensory’ nervous systems, motor and cerebellar nervous systems, urological / genitourinary system, vestibular system, metabolic / energy regulatory systems, neuropsychiatric / limbic system, cognitive systems, and / or central nervous system white matter and myelin maintenance systems, or any' combination thereof.

[0351] In an aspect, a disclosed method of treating a neurological disease and / or disorder can comprise administering to the subject one or more additional anti-neurological disease and / or disorder therapies. Anti-neurological disease and / or disorder therapies are limited but are known to the art. In an aspect, one or more disclosed additional anti-neurological disease and / or disorder therapies can be administered one or more times. In an aspect, one or more disclosed additional anti-neurological disease and / or disorder therapies can be administered by one or more routes of administration.

[0352] In an aspect, a disclosed method of treating a neurological disease and / or disorder can comprise administering an oligonucleotide therapeutic agent. A disclosed oligonucleotide therapeutic agent can comprise a single-stranded or double-stranded DNA, iRNA, shRNA, siRNA, mRNA, non-coding RNA (ncRNA), an antisense molecule, miRNA, a morpholino, a peptide-nucleic acid (PNA), or an analog or conjugate thereof. In an aspect, a disclosed oligonucleotide therapeutic agent can be an ASO or an RNAi. In an aspect, a disclosed oligonucleotide therapeutic agent can comprise one or more modifications at any position applicable. In an aspect, a disclosed oligonucleotide therapeutic agent can comprise a CRISPR-based endonuclease. In an aspect, a disclosed endonuclease can be Cas9. CRISPR / Cas9 systems and methods are known to the art.GW173 (091019-869493)

[0353] In an aspect, a disclosed method of treating a neurological disease and / or disorder can comprise administering one or more additional agents or additional therapeutic agents to the subject. Examples of such agents include, but are not limited to, the following: anticholinergics, such as trihexyphenidyl (Ariane"), benztropine (Cogentin®), ethopropazine (Parsitan®); benzodiazepines, such as diazepam (Valium®), clonazepam (Klonopin®), lorazepam (Ativan®); baclofen (Lioresal®), dopaminergic agents such as levodopa (Sinemet®) and bromocriptine (Parlodel®); tetrabenazine (Xenazine®), dopamine-depleting agents, ritonavir, lopinavir, and the like. Other agents that treat, prevent, inhibit, and / or ameliorate symptoms and / or complications of a neurological disorder and / or a neurodegenerative disease include the following: Acamprosate tablets (Campral EC). Adrenaline (epinephrine) (Emerade, EpiPen. Jext), Agomelatine tablets (Valdoxan), Almotriptan (Almogran), Amantadine, Amisulpride (Solian), Amitriptyline (Elavil), Apomorphine (APO-go, Dacepton), Aripiprazole (Ability), Aripiprazole long-acting injection (Ability7Maintena), Asenapine tablets (Sycrest), Atomoxetine (Strattera), Baclofen (Lyflex, Lioresal), Botulinum toxin type A (Botox). Bromocriptine (Parlodel), Buccal midazolam (Buccolam, Epistatus), Buprenorphine (BuTrans, Hapoctasin, Temgesic, Tephine, Transtec), Buspirone, Cabergoline tablets (Dostinex, Cabaser), Carbamazepine (Curatil, Tegretol), Chlordiazepoxide (Librium), Chlorpromazine, Citalopram (Cipramil, Celexa), Clobazam (Frisium, Perizam, Tapclob, Zacco), Clomethiazole, Clomipramine, Clonazepam, Clozapine (Clozaril, Denzapine, Zaponex), Co-beneldopa (Madopar), Co-careldopa (Sinemet), Dantrolene (Dantrium), Dexamfetamine (Amfexa), Diazepam (Diazemuls, Stesolid), Divalproex sodium (Depakote), Donepezil (Aricept), Doxepin capsules, Duloxetine (Cymbalta, Depalta, Duciltia), Eletriptan (Relpax), Entacapone (Comtess), Escitalopram (Cipralex), Eslicarbazepine (Zebinix), Ethosuximide, Fingolimod capsules (Gilenya), Fluoxetine (Olena. Prozac, Prozep). Flupentixol long-acting injection (Depixol, Psytixol), Flupentixol tablets (Depixol, Fluanxol), Fluphenazine long-acting injection (Modecate), Fluvoxamine tablets (Faverin), Frovatriptan for migraine (Migard), Gabapentin (Neurontin), Galantamine (Acumor, Consion, Elmino, Gaalin, Galsya, Galzemic, Gatalin, Gazylan, Lotprosin, Luventa, Reminyl), Haloperidol (Haldol, Serenace), Haloperidol long-acting injection (Haldol Decanoate), Hydromorphone (Palladone). Imipramine tablets and liquid medicine, Lacosamide (Vimpat), Lamotrigine (Lamictal), Levetiracetam for epilepsy (Keppra, Desitrend), Levomepromazine tablets (Nozinan), Lisdexamfetamine (Elvanse), Lithium tablets and liquid medicine (Camcolit, Liskonum, Priadel, Li-Liquid), Lofepramine, Loprazolam. Lorazepam. Lormetazepam tablets, Lurasidone (Latuda), Melatonin tablets (Circadin, Slenyto), Memantine (Ebixa, Nemtadine), Methylphenidate (Concerta, Equasym, Medikinet, Ritalin, Tranquilyn), Mianserin, Midodrine (Bramox), Mirtazapine (Zispin SolTab),GW173 (091019-869493)Moclobemide (Manerix). Modafinil tablets (Provigil), Morphine (Morphgesic. Oramorph, Zomorph), Naratriptan (Naramig), Neostigmine, Nitrazepam (Mogadon), Nortriptyline tablets, Olanzapine (Zalasta, Zyprexa), Olanzapine long-acting injection (Zypadhera), Orlistat capsules (Alli, Beacita, Orlos, Xenical), Orphenadrine, Oxazepam, Oxcarbazepine (Trileptal), Oxycodone (Abtard, Longtec, OxyContin, OxyNorm, Shortec), Paliperidone (Invega), Paliperidone long-acting injection (Xeplion, Trevicta), Paroxetine (Seroxat), Perampanel (Fy compa), Pergolide, Pericyazine, Phenobarbital, Phenytoin (Epanutin), Piracetam (Nootropil), Pizotifen tablets, Pramipexole tablets (Mirapexin, Oprymea, Pipexus, Glepark), Pregabalin (Alzain, Axalid, Lecaent, Lyrica), Primidone, Prochlorperazine (Buccastem, Stemetil), Procyclidine (Kemadrin), Pyridostigmine (Mestinon), Quetiapine (Seroquel). Rasagiline (Azilect), Reboxetine tablets (Edronax), Risperidone (Risperdal), Risperidone long-acting injection (Risperdal Consta), Rivastigmine (Alzest, Exelon, Nimvastid), Rizatriptan for migraine (Maxalt), Ropinirole tablets (Requip, Adartrel), Rotigotine patches (Neupro), Rufinamide for epilepsy (Inovelon), Selegiline (Eldepryl). Sertraline (Lustral, Zoloft), Sodium oxybate (Xyrem), Sodium valproate (Epilim, Episenta, Epival, Convulex), Sulpiride, Sumatriptan (Imigran), Temazepam, Tetrabenazine tablets (Tardiben, Xenazine), Tiagabine (Gabitril), Tizanidine, Tolcapone (Tasmar), Topiramate (Topamax), Topiramate (Topamax), Trazodone (Molipaxin), Trihexyphenidyl, Trimipramine, Valproate semisodium (Belvo, Depakote, Syonell), Venlafaxine (Efexor XL, Effexor XR), Vigabatrin (Sabril, Kigabeq), Vortioxetine (Brintellix), Zolmitriptan (Zomig), Zolpidem tablets (Stilnoct), Zonisamide (Zonegran, Desizon), Zopiclone tablets (Zimovane), and Zuclopenthixol (Clopixol). In an aspect, any one or combination of these agents can be a therapeutic agent or an additional agent used in a disclosed method.

[0354] In an aspect, a disclosed method of treating a neurological disease and / or disorder of can further comprise subjecting the subject to one or more invasive or non-invasive diagnostic assessments. Diagnostic assessments are known to the art. In an aspect, a disclosed non-invasive diagnostic assessment can comprise x-rays, computerized tomography (CT) scans, magnetic resonance imaging (MRI) scans, ultrasounds, positron emission tomography (PET) scans, or any combination thereof. In an aspect, a disclosed invasive diagnostic assessment can comprise a tissue biopsy (including a liquid biopsy and / or a solid tissue biopsy) or exploratory surgery.

[0355] In an aspect, a disclosed method of treating a neurological disease and / or disorder can restore one or more aspects of cellular homeostasis and / or cellular functionality' and / or metabolic dysregulation in a subject, such as, for example, a subject having a neurological disease and / or disorder or a neurological disease and / or disorder. In an aspect, a disclo...

Claims

GW173 (091019-869493)IX. CLAIMSWhat is claimed is:

1. A compound or pharmaceutically acceptable salt thereof according to Formula (I):wherein:n is an integer from 1 to 6;Ri is Ci-C 12 substituted alkyl, C3-C5 substituted cycloalky l, or C3-C5 substituted heterocyclyl;R2 is hydrogen or -OR3;R3 is hydrogen, polyalkylene oxide, or substituted amide; and* denotes a chiral carbon.

2. The compound of Claim 1, wherein n is 5.

3. The compound of Claim 1, wherein R2 is hydrogen or -OR3.

4. The compound of Claim 1, wherein R3 is hydrogen or poly alkylene oxide.

5. The compound of Claim 4, wherein the polyalkylene oxide is — (O — C L — CFL o — .

6. The compound of Claim 1, wherein R3 is substituted amide.

7. The compound of Claim 6, wherein the substituted amide is -C(O)NHCCH.

8. The compound of Claim 1, Ri iswherein m is 1 to 10.

9. The compound of Claim 1, wherein n is 5, R2 is -OR3, and according to Formula (II):GW173 (091019-869493)wherein:Ri is Ci-C 12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl; andR3 is hydrogen, polyalkylene oxide, or substituted amide.

10. The compound of Claim 9, wherein R3 is hydrogen or -(CH2-CH2-O)3-CH3.

11. The compound of Claim 9, wherein the substituted amide -C(O)NHCC2H.

12. The compound of Claim 9, wherein Ri iswherein m is 1 to 10.

13. The compound of Claim 1, wherein the compound isGW173 (091019-869493)14. The compound of Claim 1, wherein the compound is15. A compound or pharmaceutically acceptable salt thereof according to Formula (I):wherein:n is an integer from 1 to 6;Ri is Ci-C 12 substituted alkyl, C3-C5 substituted cycloalkyl, or C3-C5 substituted heterocyclyl;R2 is hydrogen or -OR3;R3 is hydrogen, polyalkylene oxide, or substituted amide; and* denotes a chiral carbon;with the proviso that the compound is not (3S,6S,9S,15aR)-6,9-Dibenzyl-3-(6- oxo-6-((2S,3R)-3-undecyloxiran-2-yl)hexyl)octahydro-2H-pyrido[l, 2-a][l, 4, 7, 10]tetraazacyclododecine-l,4,7,10(3H,12H)-tetraone or (3S,6S,9S,12R)-3,6-GW173 (091019-869493)dibenzy l-9-[6-[(2S)-oxiran-2-y 1] -6-oxohexy 1] - 1,4,7,10- tetr azabi cyclo[10.4.0]hexadecane-2,5, 8, 11 -tetrone.

16. A pharmaceutical formulation comprising one or more compounds of any of Claims 1 - 15, and one or more pharmaceutically acceptable carriers.

17. A method of treating cancer, slowing disease progression, and / or reducing tumor grow th and migration, the method comprising: administering to a subject having cancer a therapeutically effective amount of the pharmaceutical formulation of Claim 1 .

18. The method of Claim 17, wherein following the administering step, (i) the subject’s survivability is prolonged, (ii) the length of time before metastasis is increased, (iii) the risk of metastases is reduced, (iv) the likelihood of surgical intervention is reduced, (v) the need for administration of one or more additional therapeutic agents or regimens is reduced, (vi) the size of one or more tumors in the subject is reduced, (vii) one or more tumors in the subject are eliminated and / or reduced in size, (viii) the prevalence of one or more genomic aberrations is reduced or eliminated, (ix) the normal metabolism of one or more organ systems in the subject is restored, (x) one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation are restored, (xi) aberrant angiogenesis and / or vasculogenesis in one or more tissues and / or organs of the subject is reduced and / or inhibited, (xii) tumor growth is decreased and / or suppressed, (xiii) one or more symptoms associated with the subject’s cancer is ameliorated and / or eliminated, (xiv) the onset of one or more symptoms of the subject’s cancer can is delayed, (xv) tumor cell migration is decreased and / or diminished, (xvi) tumor cell proliferation is decreased and / or diminished, or (xvii) any combination thereof.

19. The method of Claims 17 or 18. further comprising administering to the subject one or more additional anti-cancer therapies.

20. The method of Claim 19, wherein the one or more anti-cancer therapies comprises endocrine therapy, radiotherapy, hormone therapy, gene therapy, thermal therapy, ultrasound therapy , or any combination thereof.

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