Compositions comprising GSK-3 and / or beta-catenin inhibitors and / or degraders and methods of use thereof

Abstract

The present disclosure relates to compositions and methods of suppressing or inhibiting Glycogen Synthase Kinase 3 (GSK-3) and / or β-catenin (beta-catenin). In some aspects, inhibition of GSK-3 and / or β-catenin treats, prevents, or ameliorates a GSK-3 or β-catenin related disease in a subject. In some aspects, provided herein is a method of identifying synergistic modulation of GSK-3.

Description

[0001]Attorney Docket No.047162-7509WO1(02574) TITLE Compositions Comprising GSK-3 and / or Beta-Catenin Inhibitors and / or Degraders and Methods of Use Thereof CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No.63 / 651,310, filed May 23, 2024, and U.S. Provisional Patent Application No. 63 / 727,288, filed December 3, 2024, each of which is incorporated herein by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under GM150502 and GM138722 awarded by National Institutes of Health. The government has certain rights in the invention. SEQUENCE LISTING The XML file named “047162-7509WO1 - Sequence Listing.xml” created on May 16, 2025, comprising 38,160 bytes, is hereby incorporated by reference in its entirety. BACKGROUND Protein kinase Glycogen Synthase Kinase (GSK-3) is an important player in many cellular processes, and its inhibition has the potential to treat a range of human diseases including: cancer, COVID-19, bipolar disorder, Alzheimer's disease, various metabolic disorders such as diabetes, chronic inflammatory disease, and myotonic dystrophy. GSK-3α and GSK-3β isoforms of GSK-3 are expressed in practically all human tissue and organs further establishing its importance in biology. Thus, there is a need in the art for compositions which can inhibit GSK-3 effectively. The present disclosure addresses this unmet need. BRIEF SUMMARY In one aspect, the disclosure provides a method of treating, preventing, and / or ameliorating a disease associated with an overactive or dysregulated Glycogen Synthase Kinase 3 (GSK-3) in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one of Alectinib and Gilteritinib, and a - 1 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) therapeutically effective amount of a compound of Formula (I), or a salt, solvate, prodrug, stereoisomer, or isotopologue thereof, wherein R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eare defined elsewhere herein: . In another aspect, the treating, preventing, and / or ameliorating coronavirus administering to the subject a therapeutically effective amount of at least one of Alectinib and Gilteritinib, and a therapeutically effective amount of compound of Formula (I), or a salt, solvate, prodrug, stereoisomer, or isotopologue thereof, wherein R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eare defined elsewhere herein, and wherein the compound of Formula (I) is not Niclosamide: . In another aspect, the treating, preventing, and / or ameliorating tumor neogenesis in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one of Alectinib and Gilteritinib, and a therapeutically effective amount of a compound of Formula (I), or a salt, solvate, prodrug, stereoisomer, or isotopologue thereof, wherein R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eare defined elsewhere herein: . In another aspect, the treating, preventing, and / or ameliorating cancer in a subject, the method comprising administering to the subject a - 2 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) therapeutically effective amount of Niclosamide and a therapeutically effective amount of at least one of Alectinib and Gilteritinib. In another aspect, the disclosure provides a method of treating, preventing, and / or ameliorating a disease associated with an overactive or dysregulated β-catenin in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one of Alectinib and Gilteritinib, and a therapeutically effective amount of a compound of Formula (I), or a salt, solvate, prodrug, stereoisomer, or isotopologue thereof, wherein R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eare defined elsewhere herein: . In another aspect, the composition comprising at least one of Alectinib and a (I), or a salt, solvate, prodrug, stereoisomer, or isotopologue thereof, and one or more pharmaceutical carriers or excipients, wherein R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eare defined elsewhere herein: . provides a method for identifying a combination of compounds which synergistically modulate Glycogen Synthase Kinase 3 (GSK-3) activity, the method comprising contacting a combination of compounds with a cell which constitutively expresses coronavirus nucleocapsid (N) and measuring phosphorylation of the nucleocapsid (N) from the cell. BRIEF DESCRIPTION OF THE FIGURES The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments of the present application. - 3 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. FIGs.1A-1G: Inhibition of host kinase GSK-3 delays progeny virus release from SARS-CoV-2-infected cells. FIG.1A: A schematic diagram of the N protein’s domain structure. The 16 potential Ser / Thr phosphorylation sites within the SR domain are indicated by the open bars below the sequence. Phosphorylation sites revealed by phosphoproteomics are indicated by the red bars (only four such studies using infected human cells are shown). FIG.1B: Supratherapeutic concentration of GSK-3 inhibitor CHIR-99021 (CHIR) is required to suppress N hyperphosphorylation. pGS, glycogen synthase (GS) pSer-641. Untagged N was transiently expressed in 293T cells. No intermediate species between hyperphosphorylated N** and hypophosphorylated N* is observable at 3mM CHIR-99021 (IC50 to inhibit N hyperphosphorylation). In vitro treatment with calf-intestinal alkaline phosphatase gradually removes phosphate from N and shifts the protein’s electrophoretic mobility from that of the N** to a position slightly lower than that of the N*. The 293T cells stably expressing the N construct with a C-terminal (Strep II)2-tag were incubated with 500mM arsenite (ARSN) for 30 min before CHIR-99021 treatment. FIG.1C: CHIR-99021 (10mM) alters SARS-CoV-2 replication kinetics in Calu-3 and Vero E6 cells. After cells are briefly inoculated with the virus with a multiplicity of infection (MOI) of 1 and thoroughly washed, culture media are sampled for infectious progeny virus at different time points: the early phase of virus release from infected cells (8-12h) is suppressed by CHIR-99021; the late release phase (>12h) is minimally affected. (Insert) Viral titers at 12h p.i. are compared between DMSO and CHIR-99021 treatment groups (n=3). *, p<0.01; ***, p<0.0001. TCID50, medium tissue culture infectious dose. FIG.1D: Suppression of virus release by CHIR-99021 is dose-dependent. Cultured Calu-3 cells are similarly infected by SARS-CoV-2 and treated with the inhibitor as in (FIG.1C), and viral titers at 12h p.i. are measured and compared (n=3). FIG.1E: CHIR-99021 (10mM) significantly reduces viral titer 48h after Calu-3 cells are infected by SARS-CoV-2 with a MOI of 0.1 (n=3). FIG.1F: A schematic diagram illustrating the early steps of SARS-CoV-2’s life cycle. Dashed line denotes the positive- sense and single-stranded viral gRNA. Dark grey circles denote 35~40 compact viral ribonucleoprotein (vRNP) complexes, or ribonucleosomes, found inside the virion. Light grey circles denote less compact ribonucleosomes that can be translated by host ribosomes. In the NMR structure of N (orange) in complex with the ubiquitin-like domain of nsp3 (blue) (PDB accession code: 7PKU), the unresolved SR region is ~10aa upstream of the a1 helix, - 4 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) and how it influences N:nsp3 binding is not clear. FIG.1G: The hyperphosphorylated N** has a greater binding affinity for nsp3 than N*. (top) The lysates of 293T cells transiently expressing N (with a C-terminal Strep2 tag), with or without CHIR-99021 (10mM) treatment, are passed through a column with immobilized nsp3 ubiquitin-like domain (with a C-terminal Flag3 tag) and eluted with free Flag peptide. (bottom) To rule out the possibility that N* could be bound to N** (e.g., through dimerization) in the cell and captured by nsp3 indirectly, cell lysates containing either N** or N* are mixed (1:1 ratio) in vitro, passed through the nsp3 column and eluted with Flag peptide. FIGs.2A-2E: The N protein of SARS-CoV-2 is primed at multiple sites within the SR domain. FIG.2A: The simple model posits two independent GSK-3 phosphorylation series (highlighted in yellow), each of which requires a separate priming phosphorylation (red). FIG.2B: Frequency with which the (S / T)s within the SR domain were mutated to a non- phosphorylatable residue during the first two years of the pandemic: the effect of the top five mutations on the sensitivity to CHIR-99021 was tested in 293T cells transiently expression the untagged mutants. All N sequences deposited in the GISAID database at the end of 2021 (~5,800,000 entries) were downloaded and analyzed (Table 1). The omicron variant harbors a double mutation within the SR domain (R203K / G204R). After it became dominant after 2021, the frequency of the other mutations within the SR domain was reduced. FIG.2C: Purification of the primed N* for mass spectroscopic analysis. WB with an anti-N antibody; Coomassie-stained gel. N with a C-terminal (Strep II)2-tag was stably expressed in 293T cells. After treatment with 3mM CHIR-99021, the cell lysate was passed through a StepTactin Sepharose column (column-1), which removed the hyperphosphorylated N**. N* did not bind to the resin, possibly due to aggregation. N* in the flow-through was unfolded by the addition of 6M urea and captured by passing through a second StepTactin column (column-2) in the presence of urea. Urea did not change the gel mobility of either N** or N*. FIG.2D: MS / MS product ion spectra of the peptide precursor ions used for mapping the phosphorylation sites and quantification. D = -98Da (-H3PO4); O = -18Da (-H2O); * = -17Da (-NH3). Monoisotopic ions are colored in blue; product ions with H3PO4 neutral loss are colored in green; other product ions are colored in red. The precursor ions correspond to singly phosphorylated peptides 196-209 (p-S206) and 192-203 (p-S194) and two different doubly phosphorylated peptides 178-191 (p-S186 / p-S188, p-S180 / p-S188). FIG.2E: Estimation of the phosphorylation site occupancy. Elution profiles of the singly phosphorylated (blue) and doubly phosphorylated (orange) peptides, as well as their unphosphorylated counterparts (np; black), from the LC-MS / MS experiment are shown. The - 5 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) + and ++ signs indicate where MS / MS product ion spectra shown in (FIG.2D) were obtained [++ is for the doubly phosphorylated (180, 188) peptide]. Phos-tag gel electrophoresis of 10mM CHIR-99021 treated sample reveals N* is a mixture of several differently phosphorylated species. (boxed) The four GSK-3 phosphorylation series within the SR domain. Majorly phosphorylated sites revealed by LC-MS / MS are indicated by grey circles (occupancy > 30%). Minor sites are indicated by open circles. FIGs.3A-3H: The mechanism of N hyperphosphorylation examined by chemical probes targeting the priming kinase(s) and by mutagenesis. FIG.3A: NCB-0846, dinaciclib and alectinib weakly inhibit N hyperphosphorylation but do not affect GS phosphorylation (pS641) in 293T cells transiently expressing the N protein with a C-terminal (Strep II)2-tag. The effects of NCB-0846 and dinaciclib plateau at 5mM and 10mM, respectively. For reasons yet unclear, the inhibitory activity of alectinib peaks at 5mM and becomes lower at 10mM. At 5mM, TNIK inhibitor KY-05009, CDK2 inhibitor olomoucine and SRPK1 inhibitor SPHINX31 have no effect on N hyperphosphorylation. Inhibitors for CDK1 (Ro- 3306), CDK9 (LDC000067), ALK (ceritinib) and CK1d / e (PF-670462) also showed no effect, suggesting that they are not involved in N hyperphosphorylation. Dinaciclib inhibits CDK1 / 2 / 5 / 9. Since Ser-188 is the only CDK site within the SR domain, and dinaciclib does not reduce its phosphorylation, CDK5 can be ruled out as a priming kinase. FIG.3B: The faster migrating band generated by NCB-0846, dinaciclib or alectinib treatment was purified and characterized by LC-MS / MS. Elution profiles of the singly phosphorylated (blue) and unphosphorylated peptides (black) containing Ser-206 (NSTPGSSRGTS206PAR) and Ser-188 (GGSQASSRSSS188RSR) are shown. The two prominent doubly phosphorylated peptides (186, 188) and (180, 188) are missing in all three samples. The effect of combining CHIR- 99021 (10mM) and alectinib (10mM) was also examined by Phos-tag gel electrophoresis. FIG.3C: Priming kinase inhibitor (1mM) increases the sensitivity of N hyperphosphorylation to CHIR-99021 in 293T cells stably expressing the (Strep II)2-tagged N. FIG.3D: The effects of two naturally occurring mutants S188L and S180I from GSK-3 series 3 were examined in 293T cells transiently expressing the untagged N. < indicates a proteolytic fragment. Combining S188L and S180I suppressed N hyperphosphorylation further. FIG.3E: The effects of three naturally occurring mutations from GSK-3 series 1 (S194L, S202I, S206F) and a mutation (T205I) found in the beta VOC adjacent to Ser-206 were examined. Combining S206F with either S194L or S188L eliminated N hyperphosphorylation. FIG.3F: The interaction between N and GSK-3 were assessed by co-IP.293T cells transiently expressing untagged Ns were lysed and immunoprecipitated using an antibody against GSK- - 6 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) 3. “x” probably represents a minor species in S194L / S206F where GSK-3 series 3 is phosphorylated. FIG.3G: A schematic model illustrating multiple contacts between N and GSK-3, which include the interaction of GSK-3 with several phosphorylated S / T(s) and the docking of a GSK-3 interacting domain (GID) slightly downstream of the SR domain. Priming phosphorylation at each contact site (e.g., Ser-206) is probably catalyzed by more than one kinase. FIG.3H: Sequence similarity among the GIDs of N, AXIN1 and FRAT1. Mutations of the shared (L / F)xx(L / A)xxRL motif partially inhibit but do not eliminate N hyperphosphorylation. The EE double mutation (L223E / L227E) slightly increases the sensitivity to GSK-3 inhibitor CHIR-99021 but has no effect on the sensitivity to priming kinase inhibitor alectinib. FIGs.4A-4J: The effect of R203M and R203K / G204R mutations on priming phosphorylation, GSK-3 mediated hyperphosphorylation, and sensitivity to kinase inhibitors. FIG.4A: R203M, commonly found in the delta VOC, suppresses priming phosphorylation at Ser-206. The hypophosphorylated mutant N*, generated by CHIR-99021 treatment and purified from 293T cells stably expressing the N protein with a C-terminal (Strep II)2-tag, was analyzed by LC-MS / MS, and the LC peaks corresponding to phosphopeptides (206), (194) and (180, 188), as well as their unphosphorylated counterparts (np) are shown. FIG. 4B: R203K / G204R of the omicron VOC enhances priming phosphorylation at Ser-206. FIG. 4C: Summary of the mutations’ effect on the ratio between the phosphorylated peptide (p) and its unphosphorylated counterpart (np). “xx” indicates the mutated residues. The WT control was conducted together with the mutants. FIG.4D: The hypophosphorylated N* species of the delta and omicron variants are analyzed by Phos-tag gel electrophoresis. CIP, calf intestinal alkaline phosphatase. FIG.4E: Both R203M and R203K / G204R increase the sensitivity of N hyperphosphorylation to CHIR-99021 in 293T cells transiently expressing the untagged mutants. FIG.4F: Enzastaurin (ENZA) is an orally available PKCb inhibitor but also potently inhibits GSK-3. Although not yet approved by FDA, enzastaurin is well tolerated by patients. The two orally available priming kinase inhibitors, NCB-0846 and alectinib (2mM), increase the sensitivity of N hyperphosphorylation to enzastaurin. However, only for the delta variant can significant inhibition (>50%) be achieved at 2mM enzastaurin, which is close to its Cmax observed in the clinical trial. Neither WT nor omicron is sufficiently inhibited by 2mM enzastaurin in the presence of priming kinase inhibitors. FIG.4G: The synergistic effect of 2mM niclosamide (NIC) and alectinib (ALEC) in suppressing N hyperphosphorylation correlates with reduced GSK-3 kinase activity and protein level in 293T cells stably expressing the strep-tagged N protein. Niclosamide does not improve the - 7 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) potency or efficacy of the other two priming kinase inhibitors (NCB-0846, dinaciclib). Neither does niclosamide change the sensitivity of N hyperphosphorylation to GSK-3 inhibitor CHIR-99021. Screening of other kinase inhibitors (5mM) known to target ALK identifies gilteritinib with a similar, albeit weaker, synergistic effect with niclosamide. Unlike alectinib or gilteritinib, midostaurin directly inhibits GSK-3α and GSK-3β, which may account for the lower band (N*). FIG.4H: In the presence of 2mM alectinib, niclosamide (NIC) reduces GSK-3α / β protein level and inhibits N hyperphosphorylation in a dose- dependent manner in 293T cells stably expressing the strep-tagged N protein. In contrast to pharmacological inhibition of GSK-3 by CHIR-99021, where 50% reduction of the total cellular kinase activity had a minimal effect (Fig.1B), N hyperphosphorylation is highly sensitive to the reduction of GSK-3α / β protein level induced by niclosamide / alectinib treatment, which raises the possibility that there could be two pools of cellular GSK-3, and the one that is responsible for N hyperphosphorylation is more sensitive to niclosamide / alectinib-induced degradation. FIG.4I: The effect of niclosamide / alectinib treatment on GSK-3 protein level is not only observed in N-expression 293T cells, but also in lung epithelial Calu-3 cells. Paradoxically, at 2mM niclosamide, β-catenin (also known as beta-catenin) also becomes degraded, suggesting that the pool of GSK-3 sequestered within the β-catenin destruction complex could be more resistant to niclosamide / alectinib-induced degradation, or niclosamide / alectinib treatment could have activated a different and GSK-3- independent pathway to reduce β-catenin protein level. FIG.4J: Combining 1mM niclosamide (NIC) and 2mM alectinib (ALEC) increases the sensitivity of N hyperphosphorylation to enzastaurin (ENZA) in 293T cells stably expressing the strep-tagged N proteins. FIGs.5A-5D: Potential GSK-3 phosphorylation sites within the central IDR. Alphacoronaviruses (FIG.5A) and betacoronaviruses (FIG.5B) evolved from an ancestral bat virus, whereas gammacoronaviruses (FIG.5C) and deltacoronaviruses (FIG.5D) had an avian origin. Some deltacoronavirus N proteins do not carry any (S / T)XXX(S / T) sequence motif or have an apparent SR domain. FIGs.6A-6C: Phosphorylation sites of Coronavirus N-protein full length (SEQ ID NO:30) detected by LC-MS / MS. FIG.6A: The entire sequence of N is covered by peptides generated through partial tryptic digestion and identified by LC-MS / MS (the C-terminal Strep tag is also covered but not shown). Resolved phosphorylation sites are indicated. FIGs. 6B-6C: MS / MS product ion spectra of the peptide precursor ions p-S2 (FIG.6B) and p-S23 (FIG.6C) used for mapping the phosphorylation sites outside the SR domain. - 8 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) FIGs.7A-7B: MS / MS product ion spectra of the peptide precursor ions p-S176 and p- S193 (FIG.7A) and p-S197, p-T198, and p-S201 (FIG.7B) used for mapping the phosphorylation sites within the SR domain of Coronavirus N-protein full length (SEQ ID NO:30) (in addition to those shown in FIG.2D). The phosphopeptide “GFYAEGSR” (p- S176) was obtained by complete tryptic digestion of the purified N* sample. FIGs.8A-8D: The effects of GSK-3 inhibitors [lithium, LY2090314 (LY)] and priming kinase inhibitors (NCB-0846, dinaciclib, alectinib) on N hyperphosphorylation were tested in 293T cells stably expressing the (Strep II)2-tagged wildtype and mutant N proteins. FIG.8A: The priming kinase inhibitors (1mM) increased the sensitivity to lithium. The dose- response relationship of lithium was also determined for the delta (R203M) and omicron (R203K / G204R) mutants. FIG.8B: A higher concentration of LY2090314 is required to inhibit the phosphorylation of N than that of an endogenous GSK-3 substrate (GS). Both delta and omicron mutants have a steeper dose-response curve (IC50~10nM), whereas the WT has a shallow titration with incomplete inhibition even at 100nM LY2090314. FIG.8C: The effect of delta and omicron mutations on the dose-response relationship between N hyperphosphorylation and priming kinase inhibitors. FIG.8D: shows Alectinib (2mM) enables Enzastaurin to completely inhibit N(Delta) hyperphosphorylation at a physiologically achievable concentration (2 mM). FIGs.9A-9B: MS / MS product ion spectra of the peptide precursor ions used for mapping and quantifying the phosphorylated Ser-206 and Ser-194 in the delta and omicron mutant N proteins. The mutated amino acids are indicated by red circles. FIGs.10A-10E: Alectinib (ALEC) enhances the inhibitory effects of niclosamide (NIC) on N hyperphosphorylation and tumor cell growth. FIG.10A: Niclosamide itself only weakly inhibits N hyperphosphorylation in 293T cells stably expressing the (Strep II)2-tagged wildtype N protein. FIG.10B: The synergistic effect between alectinib and niclosamide is unrelated to the latter’s mitochondrial uncoupling or STAT3-inhibitory activities. Treatment with 2mM alectinib and 2mM carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP) had no effect on N hyperphosphorylation. Similarly, 2mM ceritinib (ALK inhibitor) and 2mM napabucasin (STAT3 inhibitor) did not inhibit N hyperphosphorylation. FIG.10C: The contributions of proteasome and autophagy to protein degradation in 293T cells stably expressing Strep-tagged N protein. Alectinib, 2mM; niclosamide, 1mM; MG132 (proteasome inhibitor), 10mM; MRT68921 (dual autophagy kinase ULK1 / 2 inhibitor), 1mM. MG132 increased β-catenin protein level, in agreement with the known function of proteasome in degrading β-catenin. Nevertheless, MG132 had little effect on niclosamide / alectinib-induced - 9 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) β-catenin degradation. Furthermore, MG132 failed to restore the GSK-3 pool (reduced by niclosamide / alectinib treatment) that is responsible for N hyperphosphorylation. In contrast, MRT68921 partially rescued this pool of cellular GSK-3, causing an increase in the hyperphosphorylated N**. These results suggest that autophagy-mediated protein degradation could play a role in niclosamide / alectinib-induced destruction of GSK-3 / β- catenin, a mechanism consistent with the observation that niclosamide alone can activate autophagy. FIG.10D: In agreement with previous reports, at lower concentrations (~1mM), niclosamide exhibits broad cytostatic effect for many tumor cell lines. Alectinib (2mM) enhances niclosamide’s potency (IC50) against several of these cell lines. Such an enhancement could be essential in repurposing niclosamide for cancer treatment given the compound’s relatively poor pharmacokinetics [it remains challenging to achieve and maintain a plasma concentration of 1mM niclosamide for any systemic effect]. Combining alectinib (2mM) with higher concentrations of niclosamide (≥2mM) also causes significant toxicity to tumor cells. For Calu-3, the toxicity correlates with reduced β-catenin and GSK-3 protein levels (FIG.4I). In these experiments, the tumor cells were cultured for 72 hours in the following media [RPMI-1640 / 10% FBS / 1mM pyruvate (Calu-3); RPMI-1640 / 10% FBS (H1975, THP-1, 22Rv1); EMEM / 10% FBS (U-87 MG); high glucose DMEM / 10% FBS / 2% HS (MIA PaCa-2); McCoy’s 5A / 10% FBS (HCT 116)], and cell numbers were determined by CellTiter-Glo®2.0 at 0 and 72 hours. Data points below the X-axis (zero growth, or fold- change of 1) indicate reduced number of viable cells resulting from cell death. It should be noted that both Calu-3 and H1975 are ALK-negative non-small cell lung cancer (NSCLC) cell lines, which are not sensitive to treatment with alectinib alone. FIG.10E: Different from the tumor cell lines shown in FIG.10D, niclosamide is already very toxic toward colon cancer cell line HCT 116. The toxicity at 1mM niclosamide correlates with reduced GSK-3α, but not GSK-3β or β-catenin (see Western blot of cell lysates 16 hours post compound treatment). Alectinib does not significantly alter niclosamide’s toxicity or its ability to cause GSK-3 / β-catenin degradation in HCT 116 cells, suggesting that only a subset of tumors might respond to its synergistic effect with niclosamide. DETAILED DESCRIPTION Reference will now be made in detail to certain embodiments of the disclosed subject matter, examples of which are illustrated in part in the accompanying drawings. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the - 10 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) disclosed subject matter. Throughout this document, values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a range of “about 0.1% to about 5%” or “about 0.1% to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement “about X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise. Likewise, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z,” unless indicated otherwise. In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. The statement “at least one of A and B” or “at least one of A or B” has the same meaning as “A, B, or A and B.” In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting; information that is relevant to a section heading may occur within or outside of that particular section. All publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference. In the event of inconsistent usages between this document and those documents so incorporated by reference, the usage in the incorporated reference should be considered supplementary to that of this document; for irreconcilable inconsistencies, the usage in this document controls. In the methods described herein, the acts can be carried out in any order, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process. Definitions The term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit - 11 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) of a range, and includes the exact stated value or range. The term “alkyl” as used herein refers to straight chain and branched alkyl groups and cycloalkyl groups having from 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbons or, in certain embodiments, from 1 to 8 carbon atoms. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n- butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. As used herein, the term “alkyl” encompasses n-alkyl, isoalkyl, and anteisoalkyl groups as well as other branched chain forms of alkyl. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term “aryl” as used herein refers to cyclic aromatic hydrocarbon groups that do not contain heteroatoms in the ring. Thus aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In certain embodiments, aryl groups contain about 6 to about 14 carbons in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined herein. Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, a phenyl group substituted at any one or more of 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring, or a naphthyl group substituted at any one or more of 2- to 8-positions thereof. As used herein, the term “chronic inflammatory disease” refers to a disease wherein inflammation or a pro-inflammatory state is persistent in one or more cells of a subject. As used herein, the term “composition” or “pharmaceutical composition” refers to a mixture of at least one compound described herein with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration. The term “cycloalkyl” as used herein refers to cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In certain embodiments, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, - 12 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined herein. Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term “cycloalkenyl” alone or in combination denotes a cyclic alkenyl group. A "disease" is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal's health continues to deteriorate. A "disorder" in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal's state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal's state of health. As used herein, the terms “downregulating” or “suppressing” refers to decreasing or inhibiting the biochemical action (e.g. enzymatic catalysis of one or more biochemicals such as peptides or nucleotides) of an endogenous molecule such as a peptide or nucleotide. As used herein, the term “dysregulated” refers to the lack of normal function of a peptide or nucleotide (e.g. catalytic activity of a peptide or nucleotide). In some aspects, dysregulation is caused by improper post-transcriptional modification of a peptide, such as hypophosphorylation or hyperphosphorylation. In some aspects, “dysregulated” refers to a state of instability or aberrant action of a biochemical such as a protein or enzyme that is regulated by metabolites or endogenous molecules of an organism. As used herein, the terms "effective amount," "pharmaceutically effective amount" and "therapeutically effective amount" refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. As used herein, the term “expression vector” refers to a molecular entity capable of inducing a cell to generate a peptide or RNA. In some aspects, an expression vector is a - 13 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) plasmid, a viral vector, or a combination thereof. “GSK-3” refers to glycogen synthase kinase 3. In certain embodiments, the term “GSK-3” is used to refer to the gene encoding the kinase, the kinase itself, or any nucleic acid or polypeptide intermediate implicated in the biosynthesis of the kinase (e.g., mRNA transcript). As used herein, “GSK-3 isoform alpha” or “GSK-3α” refers to the alpha isoform of glycogen synthase kinase 3 having the amino acid sequence SEQ ID NO:28. “GSK-3 isoform beta” or “GSK-3β” refers to the isoform of glycogen synthase kinase 3 having the amino acid sequence of SEQ ID NO:29. The terms “halo,” “halogen,” or “halide” group, as used herein, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. The term “haloalkyl” group, as used herein, includes mono-halo alkyl groups, poly- halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3- difluoropropyl, perfluorobutyl, and the like. The term “heteroaryl” as used herein refers to aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members. A heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure. A heteroaryl group designated as a C2-heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed herein. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed herein. - 14 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) Additional examples of aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N- hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3- anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4- thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3- pyridazinyl, 4- pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6- quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5- isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7- benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3- dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2- benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6- benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3- dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro- benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro- benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1- benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl, 5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepine (10,11-dihydro-5H-dibenz[b,f]azepine-1-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-3-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-4-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like. - 15 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) The term “heteroarylalkyl” as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined herein. The term “heterocyclylalkyl” as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group as defined herein is replaced with a bond to a heterocyclyl group as defined herein. Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl. The term “heterocyclyl” as used herein refers to aromatic and non-aromatic ring compounds containing three or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S. Thus, a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof. In certain embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. A heterocyclyl group designated as a C2-heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase “heterocyclyl group” includes fused ring species including those that include fused aromatic and non-aromatic groups. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted, or can be substituted as discussed herein. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6- substituted, or disubstituted with groups such as those listed herein. - 16 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) The term “hydrocarbon” or “hydrocarbyl” as used herein refers to a molecule or functional group that includes carbon and hydrogen atoms. The term can also refer to a molecule or functional group that normally includes both carbon and hydrogen atoms but wherein all the hydrogen atoms are substituted with other functional groups. As used herein, the term “hydrocarbyl” refers to a functional group derived from a straight chain, branched, or cyclic hydrocarbon, and can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, acyl, or any combination thereof. Hydrocarbyl groups can be shown as (Ca- Cb)hydrocarbyl, wherein a and b are integers and mean having any of a to b number of carbon atoms. For example, (C1-C4)hydrocarbyl means the hydrocarbyl group can be methyl (C1), ethyl (C2), propyl (C3), or butyl (C4), and (C0-Cb)hydrocarbyl means in certain embodiments there is no hydrocarbyl group. The term "independently selected from" as used herein refers to referenced groups being the same, different, or a mixture thereof, unless the context clearly indicates otherwise. Thus, under this definition, the phrase "X1, X2, and X3are independently selected from noble gases" would include the scenario where, for example, X1, X2, and X3are all the same, where X1, X2, and X3are all different, where X1and X2are the same but X3is different, and other analogous permutations. The term “monovalent” as used herein refers to a substituent connecting via a single bond to a substituted molecule. When a substituent is monovalent, such as, for example, F or Cl, it is bonded to the atom it is substituting by a single bond. As used herein, “nucleocapsid” refers to a subelement of a virus that comprises the viral genome and multiple copies of nucleocapsid peptide coating on the surface thereof. The term “organic group” as used herein refers to any carbon-containing functional group. Examples can include an oxygen-containing group such as an alkoxy group, aryloxy group, aralkyloxy group, oxo(carbonyl) group; a carboxyl group including a carboxylic acid, carboxylate, and a carboxylate ester; a sulfur-containing group such as an alkyl and aryl sulfide group; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R)2, CN, CF3, OCF3, R, C(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)(R), C(O)N(R)2, OC(R)N(R)2, C(S)N(R)2, (CH2)0-2N(R)C(O)R, (CH2)0-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2(R), N(R)SOR2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, C(=NOR)R, and substituted or unsubstituted (C1-C100)hydrocarbyl, wherein R can be hydrogen (in examples - 17 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) that include other carbon atoms) or a carbon-based moiety, and wherein the carbon-based moiety can be substituted or unsubstituted. The term “overactive” as used herein in the context of protein or enzyme catalytic activity, refers to a protein or enzyme which exhibits an abnormally high level of activity, as compared to the basal level of catalytic activity. In certain embodiments, the term is used to describe an enzyme with an accelerated rate of catalysis or an enzyme which is constitutively active. The terms "patient," "subject," or "individual" are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In a non-limiting embodiment, the patient, subject or individual is a human. As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained. As used herein, the language "pharmaceutically acceptable salt" refers to a salt of the administered compounds prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids or bases, organic acids or bases, solvates, hydrates, or clathrates thereof. Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate). Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, malonic, saccharin, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2- hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitable pharmaceutically acceptable base addition salts of compounds described herein include, for example, ammonium salts, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, - 18 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N'-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound. As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound described herein within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compound(s) described herein, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound(s) described herein, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The "pharmaceutically acceptable carrier" may further include a pharmaceutically acceptable salt of the compound(s) described herein. Other additional ingredients that may be included in the pharmaceutical compositions used with the methods or compounds described herein are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference. - 19 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) As used herein, the term “phosphorylation assay” refers to a biochemical assay used to measure the addition, or extent of addition, of one or more phosphate groups to a protein or other molecule of interest (i.e., phosphorylation). Non-limiting examples of phosphorylation assays include chromatography-based assays, mass spectrometry-based assays, radioactive labeling assays, and non-radioactive labeling assays. In certain embodiments, techniques such as high-performance liquid chromatography (HPLC) can be used to separate phosphorylated from non-phosphorylated substrates for analysis (e.g., chromatography-based assay). In certain embodiments, the use of radioactive isotopes (e.g., (32P)-ATP) can be incorporated into a substrate and measured by autoradiography or scintillation counting to measure the degree of phosphorylation. In certain embodiments, colorimetric assays, fluorescent assays, and anti-body based assays can be utilized to measure the degree of phosphorylation of a substrate. In certain embodiments, the phosphorylated substrate is a nucleocapsid of a viral particle. In certain embodiments, the phosphorylating kinase is GSK-3, or an isoform thereof. As used herein, the term “phosphoproteomic analysis” refers to analysis of shifts in phosphorylation in one or more biomolecules following an experiment such as incubation of one or more cells. Phosphoproteomic analysis may comprise liquid chromatography mass spectroscopy (LC-MS), gas chromatography, liquid chromatography, mass spectroscopy, gel electrophoresis, or a combination thereof. The term "room temperature" as used herein refers to a temperature of about 15 °C to 28 °C. As used herein, the term “Severe Acute Respiratory Syndrome Coronavirus 2” or “SARS-CoV-2”, refers to the coronavirus responsible for the COVID-19 pandemic. As used herein, the term “small molecule” refers to a non-peptidic, non-oligomeric organic compound either synthesized in the laboratory or found in nature. The term "solvent" as used herein refers to a liquid that can dissolve a solid, liquid, or gas. Non-limiting examples of solvents are silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids. The term "substantially" as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 9“.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. The term "substantially free of" as used herein can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that the composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, - 20 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less. The term "substantially free of" can mean having a trivial amount of, such that a composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 0 wt%. The term “substituted” as used herein in conjunction with a molecule or an organic group as defined herein refers to the state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. The term “functional group” or “substituent” as used herein refers to a group that can be or is substituted onto a molecule or onto an organic group. Examples of substituents or functional groups include, but are not limited to, a halogen (e.g., F, Cl, Br, and I); an oxygen atom in groups such as hydroxy groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO, NO2, ONO2, azido, CF3, OCF3, R, O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, S(O)2R, S(O)3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, C(O)R, C(O)N(R)2, (CH2)0-2N(R)C(O)R, (CH2)0-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, and C(=NOR)R, wherein R can be hydrogen or a carbon-based moiety; for example, R can be hydrogen, (C1-C100)hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl; or wherein two R groups bonded to a nitrogen atom or to adjacent nitrogen atoms can together with the nitrogen atom or atoms form a heterocyclyl. The term “substrate” as used herein refers to a chemical or small organic molecule that is the target or subject of a chemical process such as enzymatic catalysis. The terms “synergy,” “synergistic modulation,” and “synergistic activity” are used interchangeably herein to refer to the combined activity of two active ingredients which is greater than the sum of the activities of each individual active ingredient. In particular, the synergy occurs when at least two substances interact in a way in which one reinforces or - 21 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) increases one or more of the effects thereof. A "therapeutic" or “therapeutically effective” treatment is a treatment administered to a subject who exhibits signs of pathology, for the purpose of diminishing or eliminating those signs. As used herein, the term "treatment" or "treating" is defined as the application or administration of a therapeutic agent, i.e., a compound or compounds as described herein (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has a condition contemplated herein or a symptom of a condition contemplated herein, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect a condition contemplated herein, or the symptoms of a condition contemplated herein. Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics. As used herein, the term “tumor neogenesis” refers to the process of a normal cell becoming pre-cancerous or cancerous. In some aspects, tumor neogenesis eventually results in a tumor or cancerous entity in a subject. As used herein, the term “variant” refers to a substantially similar gene, peptide, or RNA of a reference molecule. In some aspects, a “variant” is a mutant, splice variant, or combination thereof of a reference gene, peptide, or RNA molecule Compositions In some aspects, provided herein is a pharmaceutical composition comprising a compound of Formula (I), at least one of 9-ethyl-6,6-dimethyl-8-(4-morpholinopiperidin-1- yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Alectinib) and 6-ethyl-3-((3- methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino-5-((tetrahydro-2H- pyran-4-yl)amino)pyrazine-2-carboxamide (Gilteritinib), and one or more pharmaceutical carriers or excipients, , wherein: R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eare each independently selected from the - 22 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) group consisting of: H, halogen, NO2, CN, optionally substituted C1-C6 alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C2-C8 heteroaryl, ORA, N(RA)(RB), C(=O)RA, C(=O)ORA, C(=O)N(RA)(RB), C(=NRA)N(RA)(RB), S(=O)2ORA, S(=O)2N(RA)(RB), N(RA)C(=O)RB, N(RA)S(=O)2RB, wherein each occurrence of RAand RBis independently selected from the group consisting of optionally substituted C1-C12alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10aryl, and optionally substituted C2-C8heteroaryl. In certain embodiments, at least one of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H. In certain embodiments, at least two of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H. In certain embodiments, at least three of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H. In certain embodiments, at least four of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H. In certain embodiments, at least five of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H. In certain embodiments, at least six of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H. In certain embodiments, at least seven of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H. In certain embodiments, at least eight of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H. In certain embodiments, at least nine of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H. In certain embodiments, at least one of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are Cl. In certain embodiments, at least two of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are Cl. In certain embodiments, at least two of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are Cl. In certain embodiments, at least three of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are Cl. In certain embodiments, at least four of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are Cl. In certain embodiments, at least five of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are Cl. In certain embodiments, at least one of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are NO2. In certain embodiments, at least two of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are NO2. In certain embodiments, at least one of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are OH. In certain embodiments, at least two of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are OH. In certain embodiments, at least three of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are OH. In certain embodiments, at least one of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and - 23 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) R2eand are OC(=O)(CH2)6CH3. In certain embodiments, at least two of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are OC(=O)CH3. In certain embodiments, R1eis OC(=O)sCH3. In certain embodiments, R1ais OC(=O)(CH2)6CH3. In certain embodiments, R2cis NO2. In certain embodiments, R2cis CF3. In certain embodiments, R2cis H. In certain embodiments, R1ais OH. In certain embodiments, R1ais H. In certain embodiments, R1ais OCH3. In certain embodiments, R1bis OH. In certain embodiments, R1bis Cl. In certain embodiments, R1dis Cl. In certain embodiments, R2ais Cl. In certain embodiments, R2eis Cl. In certain embodiments, R1ais OH. In certain embodiments, R1ais H. In certain embodiments, R1ais OC(=O)(CH2)6CH3. In certain embodiments, R1bis H. In certain embodiments, R1bis Cl. In certain embodiments, R1cis H. In certain embodiments, R1dis Cl. In certain embodiments, R1dis H. In certain embodiments, R1eis H. In certain embodiments, R1eis OH. In certain embodiments, R1eis OC(=O)(CH2)6CH3. In certain embodiments, R2ais H. In certain embodiments, R2ais Cl. In certain embodiments, R2bis H. In certain embodiments, R2cis NO2. In certain embodiments, R2dis H. In certain embodiments, R2eis Cl. In certain embodiments, R2eis H. In certain embodiments, the molar ratio of the compound of Formula (I) and Alectinib is 1:1 or 1:2. In certain embodiments, the molar ratio of the compound of Formula (I) and Alectinib is 1:1. In certain embodiments, the molar ratio of the compound of Formula (I) and Alectinib is 2:1. In certain embodiments, the molar ratio of the compound of Formula (I) and Alectinib is 3:1. In certain embodiments, the molar ratio of the compound of Formula (I) and Alectinib is 4:1. In certain embodiments, the molar ratio of the compound of Formula (I) and Alectinib is 1:2. In certain embodiments, the molar ratio of the compound of Formula (I) and Alectinib is 1:3. In certain embodiments, the molar ratio of the compound of Formula (I) and Alectinib is 1:4. In certain embodiments, the compound of Formula (I) is Niclosamide (5-chloro-N-(2- chloro-4-nitrophenyl)-2-hydroxybenzamide). In certain embodiments, the compound of Formula (I) is , DK-520 (4-chloro-2-((2- octanoate). - 24 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) In certain embodiments, the molar ratio of Niclosamide and Alectinib is 1:1. In certain embodiments, the molar ratio of Niclosamide and Alectinib is 1:2. In certain embodiments, the molar ratio of Niclosamide and Alectinib is 1:3. In certain embodiments, the molar ratio of Niclosamide and Alectinib is 1:4. In certain embodiments, the molar ratio of Niclosamide and Alectinib is 2:1. In certain embodiments, the molar ratio of Niclosamide and Alectinib is 3:1. In certain embodiments, the molar ratio of Niclosamide and Alectinib is 4:1. In certain embodiments, the molar ratio of Niclosamide and Gilteritinib is 1:1. In certain embodiments, the molar ratio of Niclosamide and Gilteritinib is 1:2. In certain embodiments, the molar ratio of Niclosamide and Gilteritinib is 1:3. In certain embodiments, the molar ratio of Niclosamide and Gilteritinib is 1:4. In certain embodiments, the molar ratio of Niclosamide and Gilteritinib is 2:1. In certain embodiments, the molar ratio of Niclosamide and Gilteritinib is 3:1. In certain embodiments, the molar ratio of Niclosamide and Gilteritinib is 4:1. In certain embodiments, the molar ratio of Niclosamide and the combination of Alectinib and Gilteritinib is 1:1. In certain embodiments, the molar ratio of Niclosamide and the combination of Alectinib and Gilteritinib is 1:2. In certain embodiments, the molar ratio of Niclosamide and the combination of Alectinib and Gilteritinib is 1:3. In certain embodiments, the molar ratio of Niclosamide and the combination of Alectinib and Gilteritinib is 1:4. In certain embodiments, the molar ratio of Niclosamide and the combination of Alectinib and Gilteritinib is 2:1. In certain embodiments, the molar ratio of Niclosamide and the combination of Alectinib and Gilteritinib is 3:1. In certain embodiments, the molar ratio of Niclosamide and the combination of Alectinib and Gilteritinib is 4:1. In certain embodiments, the pharmaceutical composition is a solvate. In certain embodiments, the solvate is an aqueous solvate. In certain embodiments, the solvate has a concentration of a compound of Formula (I) of about 0.01 to 10 mM. In certain embodiments, the solvate has a concentration of a compound of Formula (I) of about 0.1 to 10 mM. In certain embodiments, the solvate has a concentration of a compound of Formula (I) of about 1 to 10 mM. In certain embodiments, the solvate has a concentration of Alectinib of about 0.01 to 10 mM. In certain embodiments, the solvate has a concentration of Alectinib of about 0.1 to 10 mM. In certain embodiments, the solvate has a concentration of Alectinib of about 1 to 10 mM. In certain embodiments, the solvate has a concentration of Gilteritinib of about 0.01 to 10 mM. In certain embodiments, the solvate has a concentration of Gilteritinib of about 0.1 to 10 mM. In certain embodiments, the solvate has a concentration of Gilteritinib of - 25 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) about 1 to 10 mM. In certain embodiments, the solvate has a concentration of the combination of Alectinib and Gilteritinib of about 0.01 to 10 mM. In certain embodiments, the solvate has a concentration of the combination of Alectinib and Gilteritinib of about 0.1 to 10 mM. In certain embodiments, the solvate has a concentration of the combination of Alectinib and Gilteritinib of about 1 to 10 mM. In certain embodiments, the aqueous solvate has a pH of from about 6 to about 8. In certain embodiments, the aqueous solvate has a pH of from about 7 to about 9. The compositions containing the compound(s) described herein include a pharmaceutical composition comprising at least one compound as described herein and at least one pharmaceutically acceptable carrier. In certain embodiments, the composition is formulated for an administration route such as oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal, intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration. In some aspects, provided herein is a pharmaceutical composition comprising a compound provided herein and further comprising a pharmaceutically acceptable excipient. Preparation of Compounds Compounds described herein can be prepared using synthetic method known by those skilled in the art. The following examples illustrate non-limiting embodiments of the compound(s) described herein and their preparation. The compounds described herein can possess one or more stereocenters, and each stereocenter can exist independently in either the (R) or (S) configuration. In certain embodiments, compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In certain embodiments, a mixture of one or more isomer is utilized as the therapeutic compound described herein. In other embodiments, compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including - 26 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) stereoselective synthesis, enantioselective synthesis and / or separation of a mixture of enantiomers and / or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography. The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having the structure of any compound(s) described herein, as well as metabolites and active metabolites of these compounds having the same type of activity. Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates and the like. In certain embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, and ethanol. In other embodiments, the compounds described herein exist in unsolvated form. In certain embodiments, the compound(s) described herein can exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In certain embodiments, compounds described herein are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In other embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, sites on, for example, the aromatic ring portion of compound(s) described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the aromatic ring structures may reduce, minimize or eliminate this metabolic pathway. In certain embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alkyl group. Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and are not limited to2H,3H,11C,13C,14C,36Cl,18F,123I,125I,13N,15N,15O,17O,18O,32P, and35S. In certain embodiments, isotopically-labeled compounds are useful in drug and / or substrate tissue distribution studies. In other embodiments, substitution with heavier isotopes such as - 27 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements). In yet other embodiments, substitution with positron emitting isotopes, such as11C,18F,15O and13N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. In certain embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. The compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser & Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4thEd., (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as described herein are modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formula as provided herein. Compounds described herein are synthesized using any suitable procedures starting from compounds that are available from commercial sources, or are prepared using procedures described herein. In certain embodiments, reactive functional groups, such as hydroxyl, amino, imino, thio or carboxy groups, are protected in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. In other embodiments, each protective group is removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal. In certain embodiments, protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and are used to - 28 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl, in the presence of amines that are blocked with acid labile groups, such as t-butyl carbamate, or with carbamates that are both acid and base stable but hydrolytically removable. In certain embodiments, carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or are blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co- existing amino groups are blocked with fluoride labile silyl carbamates. Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and are subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid is deprotected with a palladium-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and does not react. Once released from the resin, the functional group is available to react. Typically blocking / protecting groups may be selected from allyl, benzyl (Bn), benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), methyl, ethyl, t-butyl, t- butyldimethylsilyl (TBDMS), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), t-butyloxycarbonyl (Boc), para-methoxybenzyl (PMB), triphenylmethyl (trityl), acetyl, and fluorenylmethoxycarbonyl (FMOC). Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure. Methods Provided herein are methods of treating disease based on modifying the biochemical action of Glycogen Synthase Kinase 3 (GSK-3). GSK-3 has multiple isoforms including - 29 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) GSK-3 alpha isoform and beta isoform as well as splice variants thereof. GSK-3 is expressed in many relevant cells and plays an important role in the pathogenesis of multiple diseases. Thus, GSK-3 is a valuable target for inhibition by a therapeutic agent or mixture. In one aspect, the disclosure provides a method of treating, preventing, and / or ameliorating a disease associated with an overactive or dysregulated Glycogen Synthase Kinase 3 (GSK-3) in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one of Alectinib and Gilteritinib, and a therapeutically effective amount of a compound of Formula (I), or a salt, solvate, prodrug, stereoisomer, or isotopologue thereof: , wherein: 1a R , R1b, R1c, R1d, are independently selected from the group consisting of: H, halogen, NO2, CN, optionally substituted C1-C6alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C2-C8 heteroaryl, ORA, N(RA)(RB), C(=O)RA, C(=O)ORA, C(=O)N(RA)(RB), C(=NRA)N(RA)(RB), S(=O)2ORA, S(=O)2N(RA)(RB), N(RA)C(=O)RB, N(RA)S(=O)2RB, wherein each occurrence of RAand RBis independently selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C6-C10aryl, and optionally substituted C2-C8 heteroaryl. In another aspect, the disclosure provides a method of treating, preventing, and / or ameliorating a disease associated with an overactive or dysregulated β-catenin in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one of Alectinib and Gilteritinib, and a therapeutically effective amount of a compound of Formula (I), or a salt, solvate, prodrug, stereoisomer, or isotopologue thereof: - 30 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) , wherein: R1a, R1b, R1c, R1d, R1e, independently selected from the group consisting of: H, halogen, NO2, CN, optionally substituted C1-C6 alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C2-C8 heteroaryl, ORA, N(RA)(RB), C(=O)RA, C(=O)ORA, C(=O)N(RA)(RB), C(=NRA)N(RA)(RB), S(=O)2ORA, S(=O)2N(RA)(RB), N(RA)C(=O)RB, N(RA)S(=O)2RB, wherein each occurrence of RAand RBis independently selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C6-C10aryl, and optionally substituted C2-C8 heteroaryl. In another aspect, the disclosure provides a method of treating, preventing, and / or ameliorating coronavirus infection in a subject comprising administering a therapeutically effective amount of a compound of Formula (I), or a salt, solvate, prodrug, stereoisomer, or isotopologue thereof, and a therapeutically effective amount of at least one of Alectinib and Gilteritinib. In another aspect, the disclosure provides a method of treating, preventing, and / or ameliorating tumor neogenesis in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a salt, solvate, prodrug, stereoisomer, or isotopologue thereof, and a therapeutically effective amount of at least one of Alectinib and Gilteritinib. In another aspect, the disclosure provides a method of treating, preventing, and / or ameliorating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of Niclosamide and a therapeutically effective amount of at least one of Alectinib and Gilteritinib. In certain embodiments, the cancer is selected from the group consisting of leukemia, soft tissue carcinoma, glioblastoma, bone cancer, head and neck cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, pituitary adenoma, adenocarcinoma, oral cancer, - 31 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) esophageal cancer, gastric cancer, intestinal cancer, colon cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, liver cancer, lung cancer, breast cancer, and prostate cancer. In another aspect, the disclosure provides a method of downregulating or suppressing GSK-3 in a subject comprising administering a therapeutically effective amount of a compound of Formula (I) and a therapeutically effective amount of at least one of Alectinib and Gilteritinib. In certain embodiments, at least one of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H. In certain embodiments, at least two of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H. In certain embodiments, at least three of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H. In certain embodiments, at least four of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H. In certain embodiments, at least five of R1a, R1b, and are H. In certain embodiments, at least six of R1a, R2eand are H. In certain embodiments, at least seven of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H. In certain embodiments, at least eight of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H. In certain embodiments, at least nine of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H. In certain embodiments, at least one of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are Cl. In certain embodiments, at least two of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are Cl. In certain embodiments, at least two of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are Cl. In certain embodiments, at least three of R1a, R1b, R1c, R1d, R2d, and R2eand are Cl. In certain embodiments, at1a 1b least four of R , R , R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are Cl. In certain embodiments, at least five of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are Cl. In certain embodiments, at least one of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are NO2. In certain embodiments, at least two of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are NO2. In certain embodiments, at least one of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are OH. In certain embodiments, at least two of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are OH. In certain embodiments, at least three of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are OH. In certain embodiments, at least one of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are OC(=O)CH3. In certain embodiments, at least two of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are OC(=O)CH3. In certain embodiments, R1eis OC(=O)CH3. In - 32 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) certain embodiments, R1ais OC(=O)-CH3. In certain embodiments, R2cis NO2. In certain embodiments, R2cis CF3. In certain embodiments, R2cis H. In certain embodiments, R1ais OH. In certain embodiments, R1ais H. In certain embodiments, R1ais OCH3. In certain embodiments, R1bis OH. In certain embodiments, R1bis Cl. In certain embodiments, R1dis Cl. In certain embodiments, R2ais Cl. In certain embodiments, R2eis Cl. In certain embodiments, the compound of Formula (I) is Niclosamide (5-chloro-N-(2- chloro-4-nitrophenyl)-2-hydroxybenzamide). In certain embodiments, the compound of Formula (I) and Alectinib are in the form of a pharmaceutical composition further comprising at least one pharmaceutically acceptable carrier or excipient. In certain embodiments, the compound of Formula (I) and Gilteritinib are in the form of a pharmaceutical composition further comprising at least one pharmaceutically acceptable carrier or excipient. In certain embodiments, the compound of Formula (I) and mixture of Alectinib and Gilteritinib are in the form of a pharmaceutical composition further comprising at least one pharmaceutically acceptable carrier or excipient. In certain embodiments, the GSK-3 is GSK-3α and GSK-3β. In certain embodiments, the GSK-3 is GSK-3α. In certain embodiments, the GSK-3 is GSK-3β. In certain embodiments, the GSK-3 is GSK-3α, GSK-3β, or a splice variant thereof. In certain embodiments, the disease is selected from the group consisting of: tumor neogenesis bipolar disorder, Alzheimer's disease, a metabolic disorder, diabetes, a chronic inflammatory disease, and myotonic dystrophy. In certain embodiments, the disease is tumor neogenesis. In certain embodiments, the disease is Alzheimer’s disease. In certain embodiments, the disease is a metabolic disorder. In certain embodiments, the disease is diabetes. In certain embodiments, the disease is a chronic inflammatory disease optionally selected from: asthma, arthritis, obesity, cardiovascular disease, fibromyalgia, and intestinal inflammation. In certain embodiments, the disease is a muscular disease optionally selected from myotonic dystrophy. In certain embodiments, the coronavirus infection is severe acute respiratory syndrome coronavirus disease 2 (SARS CoV-2). In certain embodiments, the compound of Formula (I) and at least one of Alectinib and Gilteritinib are co-formulated. In certain embodiments, the Niclosamide and at least one of Alectinib and Gilteritinib are co-formulated. In certain embodiments, the compound of Formula (I) and at least one of Alectinib and Gilteritinib are co-administered. In certain embodiments, the Niclosamide and at least one of Alectinib and Gilteritinib are co- - 33 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) administered. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the compound of Formula (I) is not Niclosamide. In certain embodiments, the method further comprises administering Enzastaurin. In certain embodiments, the method further comprises administering NCB-0846. In certain embodiments, the method further comprises administering Enzastaurin and NCB- 0846. In certain embodiments, the molar ratio of Enzastaurin and the compound of Formula (I) is about 1:1. In certain embodiments, the molar ratio of Enzastaurin and the compound of Formula (I) is about 2:1. In certain embodiments, the molar ratio of Enzastaurin and the compound of Formula (I) is about 1:2. In certain embodiments, the molar ratio of the compound of Formula (I) and Alectinib is 1:1 or 1:2. In certain embodiments, the molar ratio of the compound of Formula (I) and Alectinib is 1:1. In certain embodiments, the molar ratio of the compound of Formula (I) and Alectinib is 2:1. In certain embodiments, the molar ratio of the compound of Formula (I) and Alectinib is 3:1. In certain embodiments, the molar ratio of the compound of Formula (I) and Alectinib is 4:1. In certain embodiments, the molar ratio of the compound of Formula (I) and Alectinib is 1:2. In certain embodiments, the molar ratio of the compound of Formula (I) and Alectinib is 1:3. In certain embodiments, the molar ratio of the compound of Formula (I) and Alectinib is 1:4. In certain embodiments, the molar ratio of the compound of Formula (I) and Gilteritinib is 1:1 or 1:2. In certain embodiments, the molar ratio of the compound of Formula (I) and Gilteritinib is 1:1. In certain embodiments, the molar ratio of the compound of Formula (I) and Gilteritinib is 2:1. In certain embodiments, the molar ratio of the compound of Formula (I) and Gilteritinib is 3:1. In certain embodiments, the molar ratio of the compound of Formula (I) and Gilteritinib is 4:1. In certain embodiments, the molar ratio of the compound of Formula (I) and Gilteritinib is 1:2. In certain embodiments, the molar ratio of the compound of Formula (I) and Gilteritinib is 1:3. In certain embodiments, the molar ratio of the compound of Formula (I) and Gilteritinib is 1:4. In certain embodiments, the molar ratio of the compound of Formula (I) and combination of Alectinib and Gilteritinib is 1:1 or 1:2. In certain embodiments, the molar ratio of the compound of Formula (I) and combination of Alectinib and Gilteritinib is 1:1. In certain embodiments, the molar ratio of the compound of Formula (I) and combination of Alectinib and Gilteritinib is 2:1. In certain embodiments, the molar ratio of the compound of Formula (I) and combination of Alectinib and Gilteritinib is 3:1. In certain embodiments, the molar ratio of the compound of Formula (I) and combination of Alectinib and Gilteritinib is - 34 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) 4:1. In certain embodiments, the molar ratio of the compound of Formula (I) and combination of Alectinib and Gilteritinib is 1:2. In certain embodiments, the molar ratio of the compound of Formula (I) and combination of Alectinib and Gilteritinib is 1:3. In certain embodiments, the molar ratio of the compound of Formula (I) and combination of Alectinib and Gilteritinib is 1:4. The methods described herein include administering to the subject a therapeutically effective amount of at least one compound described herein, which is optionally formulated in a pharmaceutical composition. In various embodiments, a therapeutically effective amount of at least one compound described herein present in a pharmaceutical composition is the only therapeutically active compound in a pharmaceutical composition. In certain embodiments, the method further comprises administering to the subject an additional therapeutic agent that treats a disease state. In certain embodiments, administering the compound(s) described herein to the subject allows for administering a lower dose of the additional therapeutic agent as compared to the dose of the additional therapeutic agent alone that is required to achieve similar results in treating a disease state in the subject. For example, in certain embodiments, the compound(s) described herein enhance(s) the activity of the additional therapeutic compound, thereby allowing for a lower dose of the additional therapeutic compound to provide the same effect. In certain embodiments, the compound(s) described herein and the therapeutic agent are co-administered to the subject. In other embodiments, the compound(s) described herein and the therapeutic agent are co-formulated and co-administered to the subject. In some aspects, provided herein is a method for identifying a combination of compounds which synergistically modulate Glycogen Synthase Kinase 3 (GSK-3) activity, the method comprising contacting a combination of compounds with a cell which constitutively expresses coronavirus nucleocapsid (N) and measuring phosphorylation of the nucleocapsid (N). In certain embodiments, the method further comprises separately contacting each compound of the combination of compounds with a cell which constitutively expresses the coronavirus nucleocapsid (N) and measuring phosphorylation of the nucleocapsid (N). In certain embodiments, the method further comprises comparing nucleocapsid (N) phosphorylation observed by contacting the combination of compounds with the cell which constitutively expresses the coronavirus nucleocapsid (N) and nucleocapsid (N) phosphorylation observed by separately contacting each compound of the combination of - 35 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) compounds with the cell which constitutively expresses the coronavirus nucleocapsid (N). In certain embodiments, the nucleocapsid (N) shares at least 85% sequence homology with SEQ ID NO:30. In certain embodiments, the nucleocapsid (N) shares at least 90% sequence homology with SEQ ID NO:30. In certain embodiments, the nucleocapsid (N) shares at least 95% sequence homology with SEQ ID NO:30. In certain embodiments, the nucleocapsid (N) shares at least 96% sequence homology with SEQ ID NO:30. In certain embodiments, the nucleocapsid (N) shares at least 97% sequence homology with SEQ ID NO:30. In certain embodiments, the nucleocapsid (N) shares at least 98% sequence homology with SEQ ID NO:30. In certain embodiments, the nucleocapsid (N) shares at least 99% sequence homology with SEQ ID NO:30. In certain embodiments, the measuring comprises subjecting a sample of the cell to liquid chromatography-mass spectroscopy (LC-MS). In certain embodiments, the combination of compounds are small organic molecules. In certain embodiments, the coronavirus is a variant of SARS CoV-2. In certain embodiments, the variant is an omicron variant. In certain embodiments, the variant is a delta variant. In certain embodiments, the variant is a beta variant. In certain embodiments, the variant is a gamma variant. In certain embodiments, the variant is an alpha variant. In certain embodiments, the cell comprises one or more HEK-293T cells. In certain embodiments, the LC-MS measurement is performed in parallel with at least one other phosphorylation measurement method (e.g., radiolabeling, non-radiolabeling, and / or chromatography). In certain embodiments, the method further comprises performing gel electrophoresis of a sample of the cell. In certain embodiments, the method comprises phosphoproteomic analysis of the cell. In certain embodiments, the phosphorylation assay is performed over the course of at least 24 hours, wherein the cell is optionally incubated for at least 24 hours. In certain embodiments, the phosphorylation assay comprises one or more GSK-3 peptides, optionally selected from GSK-3α or GSK-3β, or a variant thereof. In certain embodiments, the phosphorylation assay comprises one or more GSK-3α peptides. In certain embodiments, the phosphorylation assay comprises one or more GSK-3β peptides. In certain embodiments, the phosphorylation assay comprises one or more GSK-3α splice variants. In certain embodiments, the phosphorylation assay comprises one or more GSK-3β splice variants. - 36 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) Combination Administration and Treatment In various embodiments, a synergistic effect is observed when a compound as described herein is administered with one or more additional therapeutic agents or compounds. A synergistic effect may be calculated, for example, using suitable methods such as, for example, the Sigmoid-Emax equation (Holford & Scheiner, 1981, Clin. Pharmacokinet. 6:429-453), the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol.114:313-326) and the median-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul.22:27-55). Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively. Administration / Dosage / Formulations The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the subject either prior to or after the onset of a disease state. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation. Administration of the compositions described herein to a patient, preferably a mammal, more preferably a human, may be carried out using known procedures, at dosages and for periods of time effective to treat a disease state in the patient. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat a disease state in the patient. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dose range for a therapeutic compound described herein is from about 1 and 5,000 mg / kg of body weight / per day. One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation. Actual dosage levels of the active ingredients in the pharmaceutical compositions - 37 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) described herein may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. In particular, the selected dosage level depends upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts. A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds described herein employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the compound(s) described herein are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating such a therapeutic compound. In certain embodiments, the compositions described herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of a compound described herein and a pharmaceutically acceptable carrier. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for - 38 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin. In certain embodiments, the compositions described herein are administered to the patient in dosages that range from one to five times per day or more. In other embodiments, the compositions described herein are administered to the patient in range of dosages that include, but are not limited to, once every day, every two, days, every three days to once a week, and once every two weeks. It is readily apparent to one skilled in the art that the frequency of administration of the various combination compositions described herein varies from individual to individual depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, administration of the compounds and compositions described herein should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any patient is determined by the attending physician taking all other factors about the patient into account. The compound(s) described herein for administration may be in the range of from about 1 µg to about 10,000 mg, about 20 µg to about 9,500 mg, about 40 µg to about 9,000 mg, about 75 µg to about 8,500 mg, about 150 µg to about 7,500 mg, about 200 µg to about 7,000 mg, about 350 µg to about 6,000 mg, about 500 µg to about 5,000 mg, about 750 µg to about 4,000 mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any and all whole or partial increments therebetween. In certain embodiments, the dose of a compound described herein is from about 1 mg and about 2,500 mg. In certain embodiments, a dose of a compound described herein used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in certain embodiments, a dose of a second compound as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than - 39 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof. In various embodiments, the compound(s) described herein can be administered to a subject in an amount ranging from about 0.01 mg / kg to about 200 mg / kg, or about 0.5 mg / kg to about 190 mg / kg, or about 0.75 mg / kg to about 180 mg / kg, or about 1 mg / kg to about 170 mg / kg, or about 1.5 mg / kg to about 160 mg / kg, or about 2 mg / kg to about 150 mg / kg, or about 2.5 mg / kg to about 140 mg / kg, or about 3 mg / kg to about 130 mg / kg, or about 3.5 mg / kg to about 120 mg / kg, or about 4 mg / kg to about 110 mg / kg, or about 4.5 mg / kg to about 100 mg / kg, or about 5 mg / kg to about 95 mg / kg, or about 5.5 mg / kg to about 90 mg / kg, or about 6 mg / kg to about 85 mg / kg, or about 6.5 mg / kg to about 80 mg / kg, or about 7 mg / kg to about 75 mg / kg, or about 7.5 mg / kg to about 70 mg / kg, or about 8 mg / kg to about 65 mg / kg, or about 8.5 mg / kg to about 60 mg / kg, or about 9 mg / kg to about 55 mg / kg or about 9.5 mg / kg to about 50 mg / kg, or about 10 mg / kg to about 45 mg / kg. In various embodiments, the compound(s) described herein can be administered to a subject in an amount that is less than, equal to, or greater than about 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.25 mg / kg, 0.5 mg / kg, 0.75 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.5 mg / kg, 6 mg / kg, 6.5 mg / kg, 7 mg / kg, 7.5 mg / kg, 8 mg / kg, 8.5 mg / kg, 9 mg / kg, 9.5 mg / kg, 10 mg / kg, 12 mg / kg, 14 mg / kg, 16 mg / kg, 18 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 100 mg / kg, 105 mg / kg, 110 mg / kg, 115 mg / kg, 120 mg / kg, 125 mg / kg, 130 mg / kg, 140 mg / kg, 145 mg / kg, 150 mg / kg, 155 mg / kg, 160 mg / kg, 170 mg / kg, 175 mg / kg, 180 mg / kg, 185 mg / kg, 190 mg / kg, 195 mg / kg, or 200 mg / kg. In certain embodiments, a composition as described herein is a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound described herein, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce one or more symptoms of a disease state or disorder in a patient. Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of - 40 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and / or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents. Routes of administration of any of the compositions described herein include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds for use in the compositions described herein can be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration. Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions described herein are not limited to the particular formulations and compositions that are described herein. Oral Administration For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent. For oral administration, the compound(s) described herein can be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable - 41 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) excipients such as binding agents (e.g., polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropyl methylcellulose); fillers (e.g., cornstarch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrates (e.g., sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate). If desired, the tablets may be coated using suitable methods and coating materials such as OPADRY™ film coating systems available from Colorcon, West Point, Pa. (e.g., OPADRY™ OY Type, OYC Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and OPADRY™ White, 32K18400). Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions. The liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxy benzoates or sorbic acid). Compositions as described herein can be prepared, packaged, or sold in a formulation suitable for oral or buccal administration. A tablet that includes a compound as described herein can, for example, be made by compressing or molding the active ingredient, optionally with one or more additional ingredients. Compressed tablets may be prepared by compressing, in a suitable device, the active ingredient in a free-flowing form such as a powder or granular preparation, optionally mixed with one or more of a binder, a lubricant, an excipient, a surface active agent, and a dispersing agent. Molded tablets may be made by molding, in a suitable device, a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least sufficient liquid to moisten the mixture. Pharmaceutically acceptable excipients used in the manufacture of tablets include, but are not limited to, inert diluents, granulating and disintegrating agents, dispersing agents, surface-active agents, disintegrating agents, binding agents, and lubricating agents. Suitable dispersing agents include, but are not limited to, potato starch, sodium starch glycollate, poloxamer 407, or poloxamer 188. One or more dispersing agents can each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w relative to weight of the dosage form. One or more dispersing agents can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w relative to weight of the dosage form. Surface-active agents (surfactants) include cationic, anionic, or non-ionic surfactants, - 42 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) or combinations thereof. Suitable surfactants include, but are not limited to, behentrimonium chloride, benzalkonium chloride, benzethonium chloride, benzododecinium bromide, carbethopendecinium bromide, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cetylpyridine chloride, didecyldimethylammonium chloride, dimethyldioctadecylammonium bromide, dimethyldioctadecylammonium chloride, domiphen bromide, lauryl methyl gluceth-10 hydroxypropyl dimonium chloride, tetramethylammonium hydroxide, thonzonium bromide, stearalkonium chloride, octenidine dihydrochloride, olaflur, N-oleyl-1,3-propanediamine, 2-acrylamido-2-methylpropane sulfonic acid, alkylbenzene sulfonates, ammonium lauryl sulfate, ammonium perfluorononanoate, docusate, disodium cocoamphodiacetate, magnesium laureth sulfate, perfluorobutanesulfonic acid, perfluorononanoic acid, perfluorooctanesulfonic acid, perfluorooctanoic acid, potassium lauryl sulfate, sodium alkyl sulfate, sodium dodecyl sulfate, sodium laurate, sodium laureth sulfate, sodium lauroyl sarcosinate, sodium myreth sulfate, sodium nonanoyloxybenzenesulfonate, sodium pareth sulfate, sodium stearate, sodium sulfosuccinate esters, cetomacrogol 1000, cetostearyl alcohol, cetyl alcohol, cocamide diethanolamine, cocamide monoethanolamine, decyl glucoside, decyl polyglucose, glycerol monostearate, octylphenoxypolyethoxyethanol CA-630, isoceteth-20, lauryl glucoside, octylphenoxypolyethoxyethanol P-40, Nonoxynol-9, Nonoxynols, nonyl phenoxypolyethoxylethanol (NP-40), octaethylene glycol monododecyl ether, N-octyl beta- D-thioglucopyranoside, octyl glucoside, oleyl alcohol, PEG-10 sunflower glycerides, pentaethylene glycol monododecyl ether, polidocanol, poloxamer, poloxamer 407, polyethoxylated tallow amine, polyglycerol polyricinoleate, polysorbate, polysorbate 20, polysorbate 80, sorbitan, sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate, stearyl alcohol, surfactin, Triton X-100, and Tween 80. One or more surfactants can each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w relative to weight of the dosage form. One or more surfactants can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w relative to weight of the dosage form. Suitable diluents include, but are not limited to, calcium carbonate, magnesium carbonate, magnesium oxide, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, and sodium phosphate, Cellactose ® 80 (75 % ^- - 43 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) lactose monohydrate and 25 % cellulose powder), mannitol, pre-gelatinized starch, starch, sucrose, sodium chloride, talc, anhydrous lactose, and granulated lactose. One or more diluents can each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w relative to weight of the dosage form. One or more diluents can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w relative to weight of the dosage form. Suitable granulating and disintegrating agents include, but are not limited to, sucrose, copovidone, corn starch, microcrystalline cellulose, methyl cellulose, sodium starch glycollate, pregelatinized starch, povidone, sodium carboxy methyl cellulose, sodium alginate, citric acid, croscarmellose sodium, cellulose, carboxymethylcellulose calcium, colloidal silicone dioxide, crosspovidone and alginic acid. One or more granulating or disintegrating agents can each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w relative to weight of the dosage form. One or more granulating or disintegrating agents can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w relative to weight of the dosage form. Suitable binding agents include, but are not limited to, gelatin, acacia, pre-gelatinized maize starch, polyvinylpyrrolidone, anhydrous lactose, lactose monohydrate, hydroxypropyl methylcellulose, methylcellulose, povidone, polyacrylamides, sucrose, dextrose, maltose, gelatin, polyethylene glycol. One or more binding agents can each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w relative to weight of the dosage form. One or more binding agents can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w relative to weight of the dosage form. Suitable lubricating agents include, but are not limited to, magnesium stearate, calcium stearate, hydrogenated castor oil, glyceryl monostearate, glyceryl behenate, mineral oil, polyethylene glycol, poloxamer 407, poloxamer 188, sodium laureth sulfate, sodium benzoate, stearic acid, sodium stearyl fumarate, silica, and talc. One or more lubricating agents can each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w relative to weight of the dosage form. One or more lubricating agents can - 44 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w relative to weight of the dosage form. Tablets can be non-coated or they may be coated using known methods to achieve delayed disintegration in the gastrointestinal tract of a subject, thereby providing sustained release and absorption of the active ingredient. By way of example, a material such as glyceryl monostearate or glyceryl distearate may be used to coat tablets. Further by way of example, tablets may be coated using methods described in U.S. Patent Nos.4,256,108; 4,160,452; and 4,265,874 to form osmotically controlled release tablets. Tablets may further comprise a sweetening agent, a flavoring agent, a coloring agent, a preservative, or some combination of these in order to provide for pharmaceutically elegant and palatable preparation. Tablets can also be enterically coated such that the coating begins to dissolve at a certain pH, such as at about pH 5.0 to about pH 7.5, thereby releasing a compound as described herein. The coating can contain, for example, EUDRAGIT ® L, S, FS, and / or E polymers with acidic or alkaline groups to allow release of a compound as described herein in a particular location, including in any desired section(s) of the intestine. The coating can also contain, for example, EUDRAGIT ® RL and / or RS polymers with cationic or neutral groups to allow for time controlled release of a compound as described herein by pH-independent swelling. Parenteral Administration For parenteral administration, the compounds as described herein may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and / or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and / or dispersing agents may be used. Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. Sterile, fixed oils are conventionally - 45 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as such as lauryl, stearyl, or oleyl alcohols, or similar alcohol. Additional Administration Forms Additional dosage forms suitable for use with the compound(s) and compositions described herein include dosage forms as described in U.S. Patents Nos.6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms suitable for use with the compound(s) and compositions described herein also include dosage forms as described in U.S. Patent Applications Nos.20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional dosage forms suitable for use with the compound(s) and compositions described herein also include dosage forms as described in PCT Applications Nos. WO 03 / 35041; WO 03 / 35040; WO 03 / 35029; WO 03 / 35177; WO 03 / 35039; WO 02 / 96404; WO 02 / 32416; WO 01 / 97783; WO 01 / 56544; WO 01 / 32217; WO 98 / 55107; WO 98 / 11879; WO 97 / 47285; WO 93 / 18755; and WO 90 / 11757. Controlled Release Formulations and Drug Delivery Systems In certain embodiments, the formulations described herein can be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations. The term sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period. The period of time may be as long as a month or more and should be a release which is longer that the same amount of agent administered in bolus form. For sustained release, the compounds may be formulated with a suitable polymer or hydrophobic material which provides sustained release properties to the compounds. As such, the compounds for use with the method(s) described herein may be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation. In some cases, the dosage forms to be used can be provided as slow or controlled- release of one or more active ingredients therein using, for example, hydropropylmethyl - 46 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions described herein. Thus, single unit dosage forms suitable for oral administration, such as tablets, capsules, gelcaps, and caplets, that are adapted for controlled-release are encompassed by the compositions and dosage forms described herein. Most controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood level of the drug, and thus can affect the occurrence of side effects. Most controlled-release formulations are designed to initially release an amount of drug that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds. The term “controlled-release component” is defined herein as a compound or compounds, including, but not limited to, polymers, polymer matrices, gels, permeable membranes, liposomes, or microspheres or a combination thereof that facilitates the controlled-release of the active ingredient. In certain embodiments, the compound(s) described herein are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation. In certain embodiments, the compound(s) described herein are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation. The term delayed release is used herein in its conventional sense to refer to a drug - 47 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) formulation that provides for an initial release of the drug after some delay following drug administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours. The term pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration. The term immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration. As used herein, short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration. As used herein, rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration. Dosing The therapeutically effective amount or dose of a compound described herein depends on the age, sex and weight of the patient, the current medical condition of the patient and the progression of a disease state in the patient being treated. The skilled artisan is able to determine appropriate dosages depending on these and other factors. A suitable dose of a compound described herein can be in the range of from about 0.01 mg to about 5,000 mg per day, such as from about 0.1 mg to about 1,000 mg, for example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day. The dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses. It is understood that the amount of compound dosed per day may be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on. - 48 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) In the case wherein the patient’s status does improve, upon the doctor’s discretion the administration of the compound(s) described herein is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). The length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is reduced to a level at which the improved disease is retained. In certain embodiments, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms and / or infection. The compounds described herein can be formulated in unit dosage form. The term “unit dosage form” refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose. Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LD50(the dose lethal to 50% of the population) and the ED50(the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50and ED50. The data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized. EXAMPLES - 49 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) Various embodiments of the present application can be better understood by reference to the following Examples which are offered by way of illustration. The scope of the present application is not limited to the Examples given herein. Materials and Method Chemical reagents The following compounds were purchased from Cayman Chemical: CHIR-99021 (CAS#: 252917-06-9), NCB-0846 (CAS#: 1792999-26-8), Dinaciclib (CAS#: 779353-01-4), Alectinib (CAS#: 1256580-46-7), Enzastuarin (CAS#: 170364-57-5), LY2090234 (CAS#: 603288-22-8), KY-05009 (CAS#: 1228280-29-2), Olomoucine (CAS#: 101622-51-9), and SPHINX31 (CAS#: 1818389-84-2). Lithium chloride was obtained from Abcam (ab120853) and sterile filtered for use in cell culture. Niclosamide was obtained from MedChemExpress (CAS#: 50-65-7). Sodium (meta)arsenite was purchased from Chem Cruz (sc-250986). Cell culture, transfection, and generation of stable cell line HEK-293T and VERO E6 cells were purchased from ATCC and cultured in Dulbecco’s Modified Eagle Medium high glucose (Gibco, 11965092) + 10% Fetal Bovine Serum (Gibco, 26140079) + 1% Penicillin / Streptomycin (Gibco, 15140-122). Calu-3 cells were purchased from ATCC and cultured in Eagle’s Minimum Essential Medium (ATCC, 30-2003) with 10% FBS and 1% Penicillin / Streptomycin. Cells were cultured in 37°C incubator with 5% CO2. The tag-free wildtype (Wuhan-hu-1) nucleocapsid protein plasmid was purchased from Addgene (#177937), and the plasmid encoding the Strep-tagged nucleocapsid protein was obtained. Transfection of 1 µg per well of plasmids encoding SARS-CoV-2 tag-free nucleocapsid protein was performed using 6 µL per well of Lipofectamine 2000 on HEK-293T cells with 70-80% confluency on 6-well plates (Invitrogen, 11668027). Compounds were added to the cells with fresh media after 6 hours of incubation with plasmids for 24-hour treatment before cell lysis and immunoblotting. HEK- 293T cells stably expressing Strep-tagged nucleocapsid protein was generated via lentiviral transduction.10 μg of the plasmid encoding the Strep-tagged nucleocapsid protein was packaged with 9.183 μg of psPAX2 (Addgene #12260) and 2.768 μg of pVSV-G (Addgene #138479) into lentiviral particles with 50 μL of Lipofectamine 2000 on 80% confluent HEK- 293T cells in 6 mL of medium. Lentivirus was harvested once after 48 hours and once after 72 hours by centrifuging the supernatant at 1,000 g for 5 minutes, filtering through 0.45 μm filter (Pall Life Sciences, 12602952) and concentrating to below 500 μL volume with Amicon - 50 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) 100k filter (Millipore, UFC82024).10,000 HEK293T cells were transduced with 30 μL of concentrated lentivirus in 1.5 mL of medium using 1 µg / ml polybrene (MilliporeSigma™, TR-1003-G). Stable cell line 293T-N was selected and cultured under 1 µg / ml puromycin (Gibco, A1113802). Monoclonal population of the 293T-N was isolated using limiting dilution method.293T-N cells at 70-80% confluency were treated with compounds for 24 hours to probe N phosphorylation with immunoblotting. SARS-CoV-2 viral infection The infection medium consisted of DMEM (high glucose) supplemented with 2% heat inactivated FBS (Gibco, 16140071), 10 mM HEPES and 1% Penicillin / Streptomycin. The SARS-CoV-2 isolate USA_WA1 / 2020 (BEI Resources, #NR-52281) was prepared. To generate SARS-CoV-2 viral stock, Vero E6 cells were used for virus propagation. Vero E6 cells were infected with SARS-CoV-2 virus at an MOI of 0.01. After three days, the medium was harvested and centrifuged at 450g for 5 minutes at 4 ºC to pellet cell debris. The supernatant was then aliquoted for storage at -80 ºC. The SARS-CoV-2 titers in viral stocks were determined in Vero E6 cells by medium tissue culture infectious dose (TCID50) assay. The TCID50 assay were performed on Vero E6 cells using end-point dilution assay. Vero E6 cells were seeded into 96-well plates in growth media and allowed to grow until reaching 80- 90% confluence. The growth medium in a 96 well plates was then replaced with 100 μL of 10-fold serial dilutions of the virus in infection medium. After incubation for 5 days in a 5% CO2incubator, each well was observed under the microscope to determine if cell death has occurred, indicating virus infection. The calculation of TCID50 value was done using the Spearman-Karber method. To examine the cytopathic effect of SARS-CoV-2, Vero E6 cells were dispensed at 104cells per well into white 96-well plates (Greiner bio-one, 655074) in infection medium and incubated for 24 hours at 37 ºC with 5% CO2. Various concentrations of CHIR-99021 were added to cells and preincubated for 2 hours. Subsequently, the plates were transferred to the BSL3 lab and infected with SARS-CoV-2 virus at a MOI of 0.01. After 3 days of incubation in 5% CO2incubator, 100 μL of CellTiter-Glo 2.0 Reagent (Promega, G9241) was added to each well. The plates were then shaken for 2 minutes and luminescence was measured using the BioTek Cytation 5 cell imaging multimode reader (Agilent). For replication kinetics assay, Vero E6 and Calu-3 cells were seeded in 6-well plates 2-3 days prior to infection. Cell counts were conducted on one representative 6-well plate before infection. The cells were then infected with SARS-CoV-2 virus at a MOI of either 1 or - 51 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) 0.1 for 2 hours. Following infection, the cells were washed three times with infection medium and subsequently replenished with infection medium containing CHIR-99021. The cells were maintained in a 5% CO2 incubator and medium samples were collected at different time points. These samples were centrifuged at 450g for 5 minutes and the supernatant was utilized for TCID50 assay. SARS-CoV-2 nucleocapsid protein purification Strep-tagged SARS-CoV-2 nucleocapsid protein with original Wuhan-hu-1 sequence was stably expressed in lentiviral-transduced cell line 293T-N. Cells were treated 24 hours after plating on 100 mm dish by 5 µM of compounds for 24 hours. Buffer A was used to lyse the cells for 15 minutes on ice and cell pellet was removed by centrifugation at max speed for 30 minutes.40 µL of Strep-Tactin®XT 4Flow high capacity resin (IBA Lifesciences, 2-5030- 002) was equilibrated by 200 µL of buffer A for 3 times in an Eppendorf tube and incubated with cell lysate supernatant overnight at 4°C. The resin was spun down at 500 x g for 2 to 5 minutes.100 µL of buffer B was used to wash the protein-bound resin 5 times before eluting (E1) the hyper-phosphorylated portion of the Nucleocapsid protein with 50 µL of buffer C containing Biotin (IBA Lifesciences, 2-1016-002). The flow-through sample containing the hypo-phosphorylated portion was added 6 M urea to enhance resin binding.30 µL of fresh Strep Tag II resin was equilibrated by 200 µL of buffer D for 3 times again and incubated with urea-treated flow through sample overnight at 4°C.100 µL of buffer E was used to wash the protein-bound resin 5 times before eluting the hypo-phosphorylated portion of the Nucleocapsid protein with 40 µL of buffer F once after 24 h and once after 48 hours (E2). Compositions of all buffers used in purification process is listed below: Buffer A: 25 mM Tris-HCl pH 8.0, 150 mM NaCl, 2 mM EDTA pH 8.0, 0.05% SDS, 1% NP-40 Buffer B: 25 mM Tris-HCl pH 8.0, 500 mM NaCl, 2 mM EDTA pH 8.0, 1% NP-40 Buffer C: 100 mM Tris-HCl pH 8.0, 150 mM NaCl, 1 mM EDTA pH 8.0, 50 mM Biotin Buffer D: 25 mM Tris-HCl pH 8.0, 150 mM NaCl, 2 mM EDTA pH 8.0, 0.05% SDS, 1% NP-40, 6 M Urea Buffer E: 25 mM Tris-HCl pH 8.0, 500 mM NaCl, 2 mM EDTA pH 8.0, 1% NP-40, 6 M Urea Buffer F: 100 mM Tris-HCl pH 8.0, 150 mM NaCl, 1 mM EDTA pH 8.0, 50 mM Biotin, 6 M Urea - 52 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) Gel electrophoresis was performed on E2 samples with NuPAGE 10% Bis-Tris protein gels (Invitrogen, NP0301) by running 7 µL of sample in each well at 150 V for 4.5 h on ice. Gels were fixed, stained and destained by following standard protocol of Coomassie Brilliant Blue G 250 Staining (SERVA Electrophoresis, 17524). After washing the gels with distilled water, the lower band (hypophosphorylated) of the N* proteins from each lane was cut and submitted for LC-MS / MS analysis. LC-MS / MS Gel slices were cut into small pieces and washed with 1 mL water on a tilt-table for 10 minutes, then washed with 1 mL 50% acetonitrile (ACN) / 100 mM NH4HCO3(ammonium bicarbonate, ABC) twice for 20 minutes. The samples were reduced by the addition of 100 µL 4.5 mM dithiothreitol (DTT) in 100 mM ABC with incubation at 37ºC for 20 minutes. The DTT solution was removed, and the samples were cooled to room temperature. The samples were alkylated by the addition of 100 µL 10 mM iodoacetamide (IAN) in 100 mM ABC with incubation at room temperature in the dark for 20 minutes. The IAN solution was removed, and the gels were washed with 1 ml 50% ACN / 100 mM ABC for 20 minutes, then washed with 1 ml 50% ACN / 25 mM ABC for 20 minutes. The gels were briefly dried by SpeedVac, then resuspended in 1 gel volume of 25 mM ABC containing 5 ng / µL of digestion grade trypsin (Promega, V5111) and incubated at 37ºC for 16 hours for a full digestion or for 15 minutes for a partial digestion, with proteolysis halted by the addition of trifluoroacetic acid (TFA) to a final concentration of 1%. The supernatants containing the tryptic peptides were transferred to new Eppendorf tubes. Residual peptides in the gel bands were extracted with 300 µl 80% ACN / 0.1% trifluoroacetic acid (TFA) for 15 minutes, then combined with the original digests and dried in a SpeedVac. Peptides were dissolved in 24 µL MS loading buffer (2% acetonitrile, 0.2% trifluoroacetic acid), with 5 µl injected for LC-MS / MS analysis. LC-MS / MS analysis was performed on a Thermo Scientific Q Exactive Plus equipped with a Waters nanoAcquity UPLC system utilizing a binary solvent system (A: 100% water, 0.1% formic acid; B: 100% acetonitrile, 0.1% formic acid). Trapping was performed at 5µl / min, 99.5% Buffer A for 3 minutes using a Waters Symmetry® C18180µm x 20mm trap column. Peptides were separated using an ACQUITY UPLC PST (BEH) C18 nanoACQUITY Column 1.7 µm, 75 µm x 250 mm (37ºC) and eluted at 300 nl / min with the following gradient: 3% buffer B at initial conditions; 5% B at 1 minute; 25% B at 45 minutes; 50% B at 65 minutes; 90% B at 70 minutes; 90% B at 75 min; return to initial conditions at 77 minutes. MS was acquired in profile mode over the 300-1,700 m / z range using 1 - 53 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) microscan, 70,000 resolution, AGC target of 3E6, and a maximum injection time of 45 ms. Data dependent MS / MS were acquired in centroid mode on the top 20 precursors per MS scan using 1 microscan, 17,500 resolution, AGC target of 1E5, maximum injection time of 100 ms, and an isolation window of 1.7 m / z. Precursors were fragmented by HCD activation with a collision energy of 28%. MS / MS were collected on species with an intensity threshold of 1E4, charge states 2-6, and peptide match preferred. Dynamic exclusion was set to 20 seconds. A few preliminary runs were collected with a slightly different gradient and +1 species included. Data was analyzed using Proteome Discoverer (version 2.5) software (Thermo Scientific) and searched in-house using the Mascot algorithm (version 2.8.0) (Matrix Science). The data was searched against the Swissprotein database with taxonomy restricted to Homo sapiens (20,377 sequences) along with a custom database containing the SARS- CoV-2-Nucleocapsid Protein WT and mutant sequences of interest. Search parameters used were trypsin digestion with up to 6 missed cleavages; peptide mass tolerance of 10 ppm; MS / MS fragment tolerance of +0.02 Da; and variable modifications of methionine oxidation, carbamidomethyl cysteine, phosphorylation on serine, threonine, or tyrosine, and deamidation on asparagine and glutamine. Normal and deco database searches were searched, with the confidence level set to 95% (p<0.05). Putative matches to phosphorylated peptides of interest were manually inspected. LC elution peaks of peptides were generated using Xcalibur Qual Browser based on corresponding m / z. Immunoblotting Cells were washed with ice-cold 1x DPBS buffer and then lysed using RIPA buffer (50 mM Tris-HCl pH 7.4, 150 mM NaCl, 1% NP-40, 0.1% SDS, 0.5% DOC, 1 mM EDTA, protease and phosphatase inhibitor cocktail). After centrifugation at max speed for 30 min, samples were collected for BCA assay (Thermo scientific, 23225) to estimate the total protein concentration of each sample. To maximally dissolve hypophosphorylated Nucleocapsid protein in gel loading samples, cell lysates were directly mixed with LDS sample buffer and 1 mM Dithiothreitol (DTT) and was boiled at 90 °C before centrifugation at max speed. Large chunks of precipitates were removed then from the cell lysate samples before running the samples through NuPAGE 10% Bis-Tris protein gels (Invitrogen, NP0301). For blotting phosphatase-treated Nucleocapsid proteins, cells were lysed using a buffer containing 50 mM Tris-HCl pH 7.4, 150 mM NaCl, 1% Triton X-100, 1 mM EDTA, protease inhibitor, and protein samples were treated with 50-100 units of Quick CIP phosphatase (New England - 54 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) Biolabs, M0525S) overnight for complete dephosphorylation. All electrophoresis were run at 150 V for 4 to 5 hours on ice until the 37 kDa protein ladder ran to the end of gel to resolve differently phosphorylated forms of the Nucleocapsid protein. Phospho-tag gels (7.5%, 17well) were purchased from FUJIFILM (192-18001) and run in the same way to resolve differently primed N* proteins. Immunoblotting was then performed with 0.45μm Immobilon-FL PVDF membranes (Millipore, IPFL00010) which were blocked by 5% non- fat milk (americanBIO, AB10109-01000) and then incubated overnight at 4°C with the following primary antibodies: Nucleocapsid protein (Cell Signaling, #33717), Strep-tagged Nucleocapsid protein (Invitrogen, MA5-37747), phospho-Glycogen Synthase (Cell Signaling, 3891S), β-actin (Cell Signaling, 8457S / 3700S), GSK-3α / β (Cell Signaling, 5676S). Secondary fluorescent antibodies (LI-COR Biosciences, D10825-15 / D10831-15) were used for visualization and imaging by an Odyssey CLx system. NSP3 Pull-down The sequence encoding the NSP3 ubiquitin-like domain 1 (Ubl1, residues 1-110) of SARS-CoV-2 was synthesized by Genscript Biotech and inserted into the pCMV-3Tag-3A plasmid, which contains a C-terminal 3xFlag tag. The construct, Flag-fused NSP3(1-110) plasmid, was transfected into 293T cell using Lipofectamine 2000 and the protein was expressed for 1-2 days. Subsequently, all cells were lysed in lysis buffer (50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 1 mM EDTA, 1% (w / v) Triton X-100 and 5% (w / v) glycerol), supplemented with protease and phosphatase inhibitors. The NSP3(1-110) protein was then immobilized on Anti-Flag M2 Affinity gel (Sigma Aldrich, A2220), and the cell lysates from stable cell line 293T-N, with or without CHIR- 99021 treatment, were passed through the gel. Following this step, the gel was washed with 10 column volumes of lysis buffer and subsequently eluted with 100 µg / mL free Flag peptide (Sigma Aldrich, F3290) in lysis buffer. Finally, all samples underwent immunoblotting analysis. GSK3 Co-IP WT nucleocapsid protein and other nucleocapsid mutant proteins were transiently expressed for 24 hours in 293T cell. All cells were harvested and lysed in lysis buffer (50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 1 mM EDTA, 1% (w / v) Triton X-100 and 5% (w / v) glycerol) supplemented with protease and phosphatase inhibitors.200 μL of each cell lysate at a total protein concentration of 1 mg / mL was incubated with 4 μL of GSK3α / β antibody - 55 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) overnight at 4ºC. Following incubation, 80 μL of 25% bead slurry Protein A MagBeads (Genscript Biotech, L00273) was added and incubated with rotation for 3 hours at 4ºC. The MagBeads were washed five times with 500 μL of cell lysis buffer using a magnetic separation rack. Finally, samples were eluted in 100 μL of 1x SDS sample buffer and boiled for 5 minutes. The eluted samples were then analyzed by SDS-PAGE followed by immunoblotting. DNA Cloning Mutations of phosphorylation sites within the SR region were generated via site- directed mutagenesis based on either the tag-free SARS-CoV-2 Nucleocapsid protein plasmid (Addgene, #177937) or the Strep-tagged SARS-CoV-2 Nucleocapsid protein plasmid (UCSF). PCR was performed with PrimeSTAR® GXL DNA Polymerase (Takara, R050A), PrimeSTAR GXL Buffer (Takara, SD1967), and dNTP Mix (Takara, SD7178).50 µL of PCR product was digested by 1μL of DpnI (NEB) for 2 hours. PCR products were purified using DNA gel extraction with NucleoSpin® Gel and PCR Clean-up kit (MACHEREY- NAGEL, 740609.10). Transformation was performed with purified PCR products in Stellar Competent Cells (Takara, 636763). Exemplary Compounds Evaluated for Synergistic Activity Compounds used in experiments were acquired through commercial vendors and of acceptable purity. The names, structures, and acronyms used are shown in Table 1. Table 1. Compounds relevant to experimental testing. Compound Name Structure Niclosamid 5-chloro-N-(2-chloro-4- e (NIC) nitrophenyl)-2-hydroxybenzamide 9-ethyl-6,6-dimethyl-8-(4- Alectinib morpholinopiperidin-1-yl)-11-oxo- (ALEC) 6,11-dihydro-5H- benzo[b]carbazole-3-carbonitrile - 56 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) 6-ethyl-3-((3-methoxy-4-(4-(4- methylpiperazin-1-yl)piperidin-1- Gilteritinib yl)phenyl)amino)-5-((tetrahydro- 2H-pyran-4-yl)amino)pyrazine-2- carboxamide 3-(1-methyl-1H-indol-3-yl)-4-(1-(1- Enzastaurin (57yridine-2-ylmethyl)piperidin-4- (ENZA) yl)-1H-indol-3-yl)-1H-pyrrole-2,5- dione (S)-3-(((3-ethyl-5-(2-(2- Dinaciclib hydroxyethyl)piperidin-1- (DINA) yl)pyrazolo[1,5-a]pyrimidin-7- yl)amino)methyl)pyridine 1-oxide 6-((2-((4-(2,4-dichlorophenyl)-5-(4- CHIR- methyl-1H-imidazol-2- 99021 yl)pyrimidin-2- (CHIR) yl)amino)ethyl)amino)nicotinonitril e N-(2-(4-(57yridine-2- ylmethyl)piperazin-1-yl)-5- SPHINX31 (trifluoromethyl)phenyl)-5- (57yridine-4-yl)furan-2- carboxamide (3-((6-(2-methoxyphenyl)pyrimidin- LDC00006 4- 7 yl)amino)phenyl)methanesulfonami de - 57 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) 5-chloro-N2-(2-isopropoxy-5- methyl-4-(piperidin-4-yl)phenyl)- Ceritinib N4-(2- (isopropylsulfonyl)phenyl)pyrimidi ne-2,4-diamine 4-(1-cyclohexyl-4-(4-fluorophenyl)- PF-670462 1H-imidazol-5-yl)pyrimidin-2- amine (1s,4s)-4-((2-((1H- NCB-0846 benzo[d]58yridine58-6- (NCB) yl)amino)quinazolin-8- yl)oxy)cyclohexan-1-ol5-(4-methylbenzamido)-2- KY-05009 (phenylamino)thiazole-4- carboxamide Olomoucin 2-((6-(benzylamino)-9-methyl-9H- e purin-2-yl)amino)ethan-1-ol (2E,5E)-5-(58yridine58-6- ylmethylene)-2-((thiophen-2- Ro-3306 ylmethyl)imino)58yridine58ine-4- one 3-(9-fluoro-2-(piperidine-1- carbonyl)-1,2,3,4-tetrahydro- LY209031 [1,4]diazepino[6,7,1-hi]indol-7-yl)- 4 (LY) 4-(imidazo[1,2-a]58yridine-3-yl)- 1H-pyrrole-2,5-dione Example 1: Studies of viral GSK-3 phosphorylation - 58 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) SARS-CoV-2, the causative agent of the COVID-19 pandemic, is an enveloped positive-sense RNA virus. The virus contains four structural proteins, spike (S), envelope (E), membrane (M) and nucleocapsid (N). A key function of the N protein is to package the viral genome and maintain virion integrity through its multivalent interactions with the single- stranded RNA, oligomerization, and binding to the envelope-embedded M protein. The N protein comprises of two independently folded domains, the N-terminal domain (NTD) and C-terminal domain (CTD), and three flanking intrinsically disordered regions (IDRs). The amino-terminal portion of the central IDR (often referred to as the linker region or LKR) is also called the SR domain due to its many Ser-Arg dipeptide sequences (FIG.1A). The monomeric NTD, dimeric CTD and positively charged SR domain all contribute to RNA binding. The CTD dimer also functions as the building block for higher order N oligomers observed inside virions. The interaction between N and M likely involves both the C-terminal IDR and CTD. In addition to its structural role, the N protein has several crucial functions within the infected cell that are related to its ability to bind and form biomolecular condensates (BMCs) with RNA. After S protein-mediated receptor binding and membrane fusion, viral genomic RNA (gRNA), in the form of tightly packed ribonucleoprotein (RNP) complexes, is delivered into the cytosol where it is translated by host ribosomes to yield nonstructural proteins (nsp1- nsp16). A major conformational change of the N oligomers is probably required to make the single-stranded RNA sterically accessible. After the nsp(s) assemble into a replication transcription complex (RTC), the RNPs are recruited to the membrane-bound supramolecular structure through direct binding between N and nsp3. The transcription of viral RNA involves a unique mechanism called template switching, which enables the production of short subgenomic RNAs (sgRNAs) that guide the synthesis of N and, later, other structural proteins. Some of the newly synthesized N concentrates at the RTC, possibly through lipid lipid phase separation (LLPS), and regulates the balanced syntheses of short sgRNAs and full-length gRNA. The final step of the virus’s life cycle involves phase separation of N and gRNA with the membrane-bound M at the nucleocapsid assembly sites and budding of mature virus into the ERGIC lumen. Besides these direct contributions to viral replication, N interacts with numerous host cell factors, e.g., stress granules, to modulate host response. Phosphorylation exerts a large effect on the complex interaction between N and RNA. Within intact virions, a minimally phosphorylated N is probably required for maintaining the compact structure of the nucleocapsid. In SARS-CoV-2 infected cells, N becomes heavily phosphorylated within the SR domain. At early stages of infection, this could function as a - 59 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) trigger for structural changes in the condensed RNP complexes to enable translation and transcription. Phosphorylation influences template switching as kinase inhibition has been found to favor the syntheses of short sgRNAs and suppress the production of full-length gRNA. The ubiquitous host cell kinase GSK-3 is responsible for N hyperphosphorylation. The presence of multiple GSK-3 phosphorylation series within the central IDR is a conserved feature of all N proteins from the alpha-, beta- and gamma-coronavirus genera (FIGs.5A- 5D). At the biochemical level, N phosphorylation could impact RNA binding directly, by neutralizing the highly basic SR domain and thus reducing its electrostatic interaction with the nucleic acid, or indirectly, by modifying the properties of the protein in oligomerization and LLPS. The biochemical mechanism of N hyper-phosphorylation is currently not well understood. Example 2: Inhibition of N’s hyperphosphorylation requires supratherapeutic concentrations of GSK-3 inhibitor When the nucleocapsid (N) protein of SARS-CoV-2 is heterologously expressed in mammalian cells, its SDS-PAGE gel mobility is conspicuously retarded due to heavy phosphorylation (the band labeled with N** in FIG.1B). Host kinase GSK-3 is primarily responsible for this hyperphosphorylation as pharmacological inhibition, or genetic ablation, of the kinase eliminated the N** band. Of the 17 potential GSK-3 sites bearing the (S / T)XXX(S / T) sequence motif (see below), 12 are clustered within the SR domain and solely responsible for the gel shift. As illustrated in FIG.1B and also previously observed, a higher than usual amount of GSK-3 inhibitor is required to suppress N hyperphosphorylation in cells. CHIR-99021, a highly selective and ATP-competitive GSK-3 inhibitor, has a Ki ~10nM. Given GSK-3’s KM for ATP (26mM), the IC50of CHIR-99021 is calculated to be around 0.8mM based on the Cheng-Prusoff equation IC50 = Ki X (1 + [ATP] / Km,ATP) (assuming a cellular ATP concentration of 2mM), which agrees with the observed titration of phosphorylated glycogen synthase (pGS) within the same N-expressing cells. The higher concentration of CHIR- 99021, Li+or other GSK-3 inhibitors, required to convert N** to the faster migrating N* suggests that N* is a superb substrate for GSK-3, and its phosphorylation requires less GSK- 3 activity than that of glycogen synthase. The observation that no intermediate band is detectable between N** and N* when GSK-3 is partially inhibited also suggests that N hyperphosphorylation is a highly cooperative process (FIG.1B). - 60 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) The effect of phase-separation with RNA on the sensitivity of N hyperphosphorylation to GSK-3 inhibition was examined (FIG.1B). When expressed in mammalian cells, N has a diffused cytoplasmic distribution but becomes localized to arsenite-induced stress granules, which are mRNA-enriched BMCs. Arsenite treatment did not lower the IC50 of CHIR-99021, suggesting that LLPS itself does not hinder GSK-3- mediated N hyperphosphorylation. Example 3: GSK-3 inhibition delays progeny virus release Earlier studies using MHV, a model animal coronavirus, implicated GSK-3-mediated N phosphorylation in the readthrough of body transcription regulatory sequence (TRS), which is essential for the syntheses of longer subgenomic mRNAs and the full-length gRNA. Surprisingly, under experimental conditions optimized for drug screening, it was found that CHIR-99021 did not protect Vero E6 cells from SARS-CoV-2-induced cytopathic effects (CPE). To better understand the impact of GSK-3 inhibition on viral replication, infected Calu-3, a human lung epithelial cell line, were infected with SARS-CoV-2 and the release of progeny virus into the culture medium was examined. Without CHIR-99021 treatment, new virus started to appear in the medium at 8h post infection (p.i.), and this early phase of viral release is followed by an exponential growth phase starting around ~12h p.i. (FIG.1C). GSK- 3 inhibition greatly suppressed the early phase of virus release but had little effect on the exponential growth phase. This response is not specific to Calu-3 cells since similar experiment in Vero E6 cells yielded identical results. Using viral tier at 12h p.i. to quantify the compound’s effect, it was found that a significant reduction is only achievable at 10mM CHIR-99021 (FIG.1D). Although these experiments by themselves are not sufficient to prove that the compound’s suppressive effect is mediated through the N protein, the dose- response relationship is consistent with the elevated IC50of CHIR-99021 in blocking N hyperphosphorylation and raises the possibility that complete inhibition of N hyperphosphorylation might be required to delay virus release (FIG.1B and FIG.1D). In agreement with a previous report, it was found that 10mM CHIR-99021 suppressed viral titer in the culture medium by >10-fold in an assay where multiple rounds of infection were involved (FIG.1E). Upon entering the cytoplasm, phosphorylation of the N protein by host kinases destabilizes the tightly packed nucleocapsid, which facilitates translation of the positive-sense viral RNA (FIG.1F). The N protein subsequently plays a role in guiding the single viral genome to the RTC by binding to nsp3. To examine the effect of GSK-3-mediated N - 61 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) hyperphosphorylation on nsp3 binding, the cell lysate containing N** and N* was passed through an affinity column with immobilized nsp3 (FIG.1G). Elution by Flag peptide revealed that the hyperphosphorylated N** outcompeted the hypophosphorylated N* in nsp3 binding, providing direct evidence that phosphorylation of the SR domain could regulate N:nsp3 binding. Without wishing to be bound by any theory, the observation that the hypophosphorylated N* retains some binding activity toward nsp3 may explain why SARS- CoV-2 can still replicate in the presence of 10mM CHIR-99021 (FIG.1G). How phosphorylation enhances N:nsp3 binding is unclear at this time as a recent NMR study maps the nsp3-binding segment to residues 219-258, which are slightly downstream of the SR domain (FIG.1F). Without wishing to be bound by any theory, it is possible that hyperphosphorylation by GSK-3 affects nsp3 binding indirectly by influencing the accessibility or the confirmation of the 219-258 segment. Coronavirus is unique among (+)RNA viruses in that its gRNA, when artificially introduced into a cell, has high infectivity only in the presence of the N protein. Using engineered MHV gRNA carrying a luciferase reporter, Koetzner and co-workers recently showed that, without N, luciferase expression was delayed but not completely suppressed. The reason behind the altered kinetics was not fully resolved, but its similarity to what was observed with CHIR-99021 treatment raises the possibility that the essential function of the N protein in supporting viral gRNA infectivity could be compromised by blocking GSK-3- mediated phosphorylation (FIG.1C). Example 4: N is primed at multiple sites before GSK-3-mediated hyperphosphorylation Most GSK-3 substrates need to be primed at the i+4 position [(S / T)XXXp(S / T)] by another Ser / Thr kinase [some substrates have multiple (S / T)XXX(S / T) sequence motifs that are joined together, e.g., S641…S645…S649…S653in glycogen synthase (GS), where priming phosphorylation of the most C-terminal (S / T) would enable GSK-3 to phosphorylate the entire series in a sequential manner]. The observation that most alpha- and beta-coronavirus N proteins harbor more than one and often long GSK-3 series within their SR domains indicates that hyperphosphorylation could be a functionally important adaptation to mammalian host (FIGs.5A-5D). It was generally believed that the N protein of SARS-CoV-2 contains at least two independent GSK-3 series, each initiated from a separate priming site (Ser-206, Ser-188; highlighted in red in FIG.2A). This hypothesis, however, seems incompatible with the observation that, early during the COVID-19 pandemic, many circulating viruses harbor N - 62 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) mutations that are predicted to disrupt the proposed GSK-3 series: e.g., replacement of Ser- 202 by a nonphosphorylatable residue would completely negate the effect of priming at Ser- 206 (FIG.2B; Tables 2A-2E). The effect of several of these mutations was studied in 293T cells. As shown in FIG.2B, none of the three Ser-202 mutations (S202I, S202N, S202R) eliminates N hyperphosphorylation, or renders N hyperphosphorylation more sensitive to CHIR-99021. T205I, a mutation occurring at the C-terminus of another GSK-3 series (series 2 in FIG.2E), and commonly found in the beta VOC, has no effect either. Interestingly, mutation of Ser-194 (S194L), which is in the same series as Ser-202 but appears in the middle, partially inhibits N hyperphosphorylation, generating a faint N* band in the absence of CHIR-99021. S194L also increases the sensitivity of N hyperphosphorylation to the GSK- 3 inhibitor, shifting its IC50 closer to the theoretical value (~1mM). For Tables 2A-2D: Sequence variations within the SR domain of SARS-CoV-2’s N protein. The a.a. number and type in the reference sequence (hCoV-19 / Wuhan / WIV04 / 2019) are shown in the top two rows. The left column contains the 20 types of amino acids (“X” indicates an unknown amino acid due to uncertainty in the deposited genome sequence). The numbers inside the table indicate how many times a particular amino acid is found at that position. Table 2A. Sequence variations within the SR domain of SARS-CoV-2’s N protein (Position 171-179). Position in sequence 171 172 173 174 175 176 177 178 179 Canonical amino acid F Y A E G S R G G A 5 0 5816 270 1 0 2 0 13 4 C 28 5 0 0 0 0 0 148 371 D 1 5 0 3 0 0 0 541 449 E 0 0 2 5825 115 1 0 2 0 0 F 5820 150 4 0 0 0 0 0 2 0 G 1 0 0 1 5827 5820 5815 402 11 90 736 476 H 0 17 0 0 0 0 0 0 0 I 54 0 2 0 0 8 39 0 0 K 0 0 0 2 0 0 113 0 0 L 97 0 0 0 0 0 0 0 0 M 0 0 0 0 0 0 0 0 0 N 0 3 0 0 0 4 0 0 0 - 63 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) P 0 0 3 0 0 0 0 0 0 Q 0 0 0 6 0 0 0 0 0 R 0 0 0 0 15 14 5825 317 40 13 S 3 1 1067 0 0 5828 314 17 465 3826 T 0 0 103 1 1 3 0 0 0 V 10 0 4269 1 4 0 0 925 1641 W 0 0 0 0 3 0 0 0 0 Y 42 5819 825 1 0 0 0 0 0 0 X 5126 5179 4993 4652 4422 4329 4607 4878 4987 1 2 5 2 6 6 4 2 2 Table 2B. Sequence variations within the SR domain of SARS-CoV-2’s N protein (Position 180-190). Position in sequence 180 181 182 183 184 185 186 187 188 189 190 Canonical amino acid S Q A S S R S S S R S 581 A 0 0 535 211 10 0 62 68 7 0 0 3 C 51 0 0 4 1 116 2 1 0 0 245 23 D 0 0 90 0 0 0 0 0 0 0 1 E 0 42 0 0 0 0 0 0 0 0 0 F 0 0 10 111 46 1 690 1 0 0 0 G 87 1 1 0 0 15 0 0 0 6 429 H 0 181 0 0 0 174 0 2 2 484 0 I 174 0 0 0 0 0 0 0 546 9 0 0 5 K 0 48 0 0 0 0 0 3 0 0 0 L 0 690 0 2 5 256 0 154 124 10 9 319 0 M 0 0 0 0 0 0 0 0 0 0 0 N 170 0 0 0 0 0 2 1 0 0 596 P 0 6 86 642 62 190 168 180 159 3 0 582 Q 0 167 1 0 0 0 0 0 0 0 0 3 582 582 R 43 126 0 0 0 181 1 0 0 029 819 9 3 581 1 7 581 582 582 580 582 581 S 873 36 4 057 428 30 127 851 152 69 348 1 1 2 8 3 0 3 - 64 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) T 419 1 273 444 0 4 0 16 30 3 0 2 V 2 0 325 0 0 2 0 0 0 2 3 W 0 0 0 2 0 0 0 0 0 0 0 Y 0 0 5 705 5 16 0 147 7 0 0 1 0 X 504 488 481 486 472 480 479 474 487 502 508 00 83 44 14 26 03 57 44 12 30 31 Table 2C. Sequence variations within the SR domain of SARS-CoV-2’s N protein (Position 191-199). Position in sequence 191 192 193 194 195 196 197 198 199 Canonical amino acid R N S S R N S T P A 2 0 0 835 0 0 18 61 2 C 273 0 99 0 0 0 0 0 0 D 0 170 0 0 0 76 0 0 0 E 0 0 0 0 2 0 0 0 0 F 0 0 0 0 0 0 1 0 0 G 4 0 218 0 100 2 0 0 0 H 1112 7 0 0 0 151 0 0 1 I 0 3 1019 6 0 6937 524 0 1695 2 K 0 185 0 1 1513 54 0 0 0 L 696 0 0 9881 129 1 1655 6 7903 3 71 M 0 0 0 0 0 0 0 0 0 N 0 5822 858 592 0 10 5825 600 1 189 0 P 7 0 0 299 0 0 555 12 5648 757 Q 0 0 0 2 0 0 2 0 257 R 5818 1 5817 934 185 0 236 1 0 0 11 S 74 115 5811 5724 230 7 5817 142 498 01 037 9 7080 T 0 14 1913 15 1003 55 1082 5826 867 277 V 0 0 3 2 0 0 1 0 2 W 0 0 0 0 0 0 0 0 0 Y 0 207 0 0 0 66 0 0 0 X 5055 4809 4730 4718 4449 4442 4505 4281 4969 0 2 4 4 2 1 2 6 2 Table 2D. Sequence variations within the SR domain of SARS-CoV-2’s N protein (Position - 65 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) 200-210). Position in sequence 200 201 202 203 204 205 206 207 208 209 210 Canonical amino acid G S S R G T S P A R M 578 A 9 2 1 0 737 118 102 12 782 1 1 4 C 305 1 192 166 8 0 0 0 44 0 1 0 0 D 686 0 0 0 0 0 1 0 130 0 0 E 0 0 0 320 1 205 0 0 0 0 2 1 F 0 0 82 0 0 0 569 3 4 10 0 0 582 429 G 239 829 483 46 543 1 1 0 657 93 1 4 0 H 0 0 0 0 0 0 0 135 0 0 0 I 0 293 134 207 157 106 1 8 3 0 16 3 7 683 0 0 0 89 42 151 K 0 0 10 029 1 1 0 0 0 176 114 2 0 L 0 0 0 40 290 2 3 142 537 8 2 0 257 339 581 M 0 0 3 477 1 2 0 0 0 1 105 6 9 N 1 504 549 0 15 0 483 0 2 0 1 1 14 0 827 581 P 1 0 101 16 45 8 014 243 0 0 6 Q 0 0 0 0 318 0 0 26 0 0 0 133 142 580 R 7 138 895 70 037 772 0 0 75 0 974 80 8 9 582 578 582 S 540 114 479 269 14 214 131 111 349 19 9 314 0 8 7 7 6 566 T 0 0 106 762 1 758 39 564 213 813 663 0 V 187 0 4 114 711 5 0 284 0 1 7 0 283 W 0 0 0 4 0 0 0 0 0 0 2 Y 0 0 17 0 0 0 126 0 0 0 0 X447 459 521 639 608 455 431 441 447 482 475- 66 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) 76 06 29 97 88 17 69 90 29 29 48 To better understand how GSK-3-mediated hyperphosphorylation of the N protein is initiated, the hypophosphorylated N* from a stable 293T cell line expressing a Strep-tagged N was purified and characterized by mass spectroscopy. LC-MS / MS analysis of the purified protein, extracted from the excised Coomassie band and partially digested by trypsin (FIG. 2C), identified a total of 14 phosphorylation sites (FIG.6A): three of these are located in the N-terminal IDR (S2, S23, S26), one within the NTD (S105), and ten inside the SR domain (S176, S180, S186, S188, S193, S194, S197, T198, S201, S206) (Table 3; FIG.2D; FIGs. 6B-6C; FIGs.8A-8C). Although several previous phosphoproteomic analyses of SARS-CoV- 2-infected cells also identified these (and other) sites, the greater amount of the purified protein sample allows us to more reliably determine the occupancy for each phosphorylation site. Table 3. GSK-3-independent phosphorylation sites within the SR domain. A total of 14 singly or doubly phosphorylated peptides, covering the entire SR domain, were observed. From these, 9 phosphosites (highlighted in rbold) could be unequivocally mapped based on the MS / MS spectrum (in the lower portion of the table, likely phosphorylation sites are highlighted in green). The relative abundance (phosphorylation stoichiometry) of the known site(s) could be estimated by comparing the areas under the LC peaks for the phosphorylated peptide (p) and its unphosphorylated counterpart (np), assuming the two peptides have similar ionization efficiency. In a separate experiment where N was thoroughly digested by trypsin, a phosphopeptide containing p-S176 was also observed. Peptides with known phosphosites Phosphosite Phosphopeptide p / np S180 GFYAEGSRGGSQASSR (SEQ ID NO:3) 0.03 S188 GGSQASSRSSSRSR (SEQ ID NO:4) 2.54 S180 & S188 GGSQASSRSSSRSR (SEQ ID NO:5) 40.19 S186 & S188 GGSQASSRSSSRSR (SEQ ID NO:6) 37.76 S193 SRNSSRNSTPGSSR (SEQ ID NO:7) 0.87 S194 NSSRNSTPGSSR (SEQ ID NO:8) 0.50 S197 NSSRNSTPGSSR (SEQ ID NO:9) 0.095 T198 SRNSSRNSTPGSSR (SEQ ID NO:10) 0.0098 S201 NSSRNSTPGSSR (SEQ ID NO:11) 0.01 S206 GTSPAR (SEQ ID NO:12) 0.23 NSTPGSSRGTSPAR (SEQ ID NO:13) 2.02 Uncertain phosphosites (single) Potential phosphosite Phosphopeptide p / np - 67 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) S180 / S183 / S184 (likely GGSQASSRSSSRSR (SEQ ID NO:14) 1.00 S180) S183 / S184 GFYAEGSRGGSQASSR (SEQ ID NO:15) 0.002 S186 / S187 (likely S186) GGSQASSRSSSRSR (SEQ ID NO:16) 0.68 S186 / S187 / S188 (likely GGSQASSRSSSR (SEQ ID NO:17) 0.37 S188) S197 / T198 NSSRNSTPGSSRGTSPAR (SEQ ID 0.02 NO:18) 0.21 SRNSSRNSTPGSSRGTSPAR (SEQ ID NO:19) S201 / S202 / T205 / S206 NSSRNSTPGSSRGTSPAR (SEQ ID 0.61 NO:20) 0.53 SRNSSRNSTPGSSRGTSPAR (SEQ ID NO:21) S201 / S202 NSTPGSSR (SEQ ID NO:22) 0.0013 T205 / S206 (likely S206) GTSPARMAGNGGDAALALLLLDR 42.32 (SEQ ID NO:23) Potential phosphosites (double) Potential phosphosite Phosphopeptide Note Suspected mixture of GGSQASSRSSSR (SEQ ID NO:24) 0.3 (180, 188) and (186, 188) S193 / S194, S197 NSSRNSTPGSSR (SEQ ID 0.021 NO:25)SRNSSRNSTPGSSR (SEQ ID 0.078 NO:26) S201 / S202 / T205, S206 NSTPGSSRGTSPAR (SEQ ID NO:27) Minor The phosphorylation stoichiometry was quantified by comparing the areas under the LC peaks for the phosphorylated peptide (p) and its unphosphorylated counterpart (np), assuming they have similar ionization efficiencies (FIG.2E; Table 3). Among the 14 identified sites, only six (S180, S186, S188, S193, S194, S206) are highly occupied, and they are all located within the SR domain (grey circles in FIG.2E). Ser-188 appears to be fully phosphorylated, and it is primarily found in two doubly phosphorylated peptides: (180, 188) and (186, 188) (the orange peak in FIG.2E). In contrast, none of the other sites has full occupancy. Ser-206 is found in two singly phosphorylated peptides, but each peptide also has a significant unphosphorylated population (p / np ratio 0.2-2; Tables 2A-2D). The possibility that N* could represent an ensemble of several differently phosphorylated species due to partial occupancy at most of the identified sites was tested by running the CHIR-99021- treated sample through a Phos-tag gel, which revealed two groups of bands: the upper group accounts for the majority of N* and may contain up to three species; the lower group contains two minor species (FIG.2E). Another interesting finding from the mass spectroscopic analysis is that Ser-194, the mutation of which inhibited N hyperphosphorylation (FIG.2B), is a major site of priming phosphorylation. - 68 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) The hyperphosphorylated N** was also purified and similarly studied by LC-MS / MS. Unfortunately, none of the identified peptides covers the SR domain, thus leaving open the question about the nature of the hyperphosphorylated state. The data, however, does reveal that there is no highly occupied phosphorylation site outside the SR domain and thus supports a previous conclusion based on deletion mutagenesis. Example 5: The biochemical mechanism of GSK3-mediated hyperphosphorylation Screening a small collection of kinase inhibitors has yielded two compounds, NCB- 0846 and dinaciclib, that weakly suppress N hyperphosphorylation in a GSK-3-independent manner (FIG.3A). LC-MS / MS analysis of the hypophosphorylated species generated by compound treatment showed that both NCB-0846 and dinaciclib inhibited priming phosphorylation at Ser-188 but had little effect on the phosphorylation of Ser-206 (FIG.3B). In agreement with their function as priming kinase inhibitors, NCB-0846 and dinaciclib increase the sensitivity of N hyperphosphorylation to GSK-3 inhibitor CHIR-99021 and lithium (FIG.3C; FIGs.8A-8C). The majority of N remains hyperphosphorylated at concentrations of NCB-0846 or dinaciclib where their effects have plateaued. To address whether this could be due to the chemical probes’ partial inhibition of Ser-188 phosphorylation, the serine was mutated to a non-phosphorylatable amino acid (FIG.3D). Intriguingly, S188L, a naturally occurring but rare mutation, generates some hypophosphorylated N* instead of converting all the N** to an intermediate species [a result like that produced by S188A]. Most of the mutant remains hyperphosphorylated, suggesting that the loss of Ser-188 priming phosphorylation could be overcome by other mechanisms. The absence of any intermediate between N* and N** supports the earlier hypothesis that N hyperphosphorylation is a highly cooperative process. Combining S188L with S180I, which eliminates the (180, 188) double phosphorylation, increases the ratio of N* over N** but does not fundamentally alter the outcome (FIG.3D). The lower efficacy of the two priming kinase inhibitors is thus likely due to (i) multiple kinases contribute to Ser-188 phosphorylation, and (ii) priming at Ser-188 is not essential for N hyperphosphorylation. Similar effect on N hyperphosphorylation is observed for another natural mutation, S206F, which eliminated the putative priming site for GSK-3 series 1 (FIG.2E; FIG.3E). An unexpected finding, however, is that when S206F is combined with S194L, which eliminated a highly phosphorylated site within the same series, N hyperphosphorylation is abolished. The effect is specific to S194L, as combining S206F with the nearby S202I or T205I does not - 69 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) produce such a drastic reduction (FIG.3E). Combining S206F with S188L also abolishes hyperphosphorylation. Co-IP with GSK-3 reveals that both S206F / S194L and S206F / S188L greatly weaken the binding between N and GSK-3 (FIG.3F). Taken together, the data suggest a model where GSK-3 engages multiple phosphorylated Ser(s) within the SR domain (FIG.3G).It was hypothesized that these redundant interactions could bypass the classic requirement of GSK-3 for a phosphorylated Ser / Thr at the i+4 position, thus explaining why, for GSK-3 series 1 at least, phosphorylation does not need to occur in a sequential manner (FIGs.2A-2B). The Co-IP experiment also shows that the hyperphosphorylated N** binds more tightly to GSK-3, raising the possibility of a positive feedback mechanism where phosphorylation could become more efficient as the reaction proceeds. Alectinib, the only other known priming kinase inhibitor, also suppresses N hyperphosphorylation in 293T cells heterologously expressing the viral protein (FIG.3A). LC-MS / MS analysis of the faster migrating N* band shows that alectinib inhibited phosphorylation at both Ser-188 and Ser-206 (FIG.3B). However, unlike S206F / S188L, alectinib only weakly inhibited N hyperphosphorylation, and it is no more efficacious than NCB-0846 or dinaciclib, suggesting again that there exist multiple priming kinases. Phos-tag gel electrophoresis of the sample treated with both CHIR-99021 and alectinib confirms that alectinib is not sufficient to reduce all the hypophosphorylated N* species to a fully dephosphorylated state (FIG.3B). Future studies are required to identify the kinase targets for NCB-0846, dinaciclib and alectinib responsible for their suppressive effect on N hyperphosphorylation (TNIK, CDK1 / 2 / 5 / 9 and SRPK1, known targets for the chemical probes, are not involved in priming phosphorylation; FIG.3A). One more mechanism to strengthen the binding between N and GSK-3 may involve a short segment of N that bears sequence similarity to the GSK-3 interacting domains (GID) of AXIN1 and FRAT1. Mutation of the hydrophobic motif (L223E, L227E) partially suppresses N hyperphosphorylation, increases its sensitivity to CHIR-99021, but has no effect on the response to priming kinase inhibitor (FIG.3H). Nevertheless, the GID appears to play a smaller role in the overall binding (FIG.3G), since reducing priming phosphorylation alone, e.g., in S206F / S188L, was found to remove most of the co-IP signal (FIG.3F). It is also intriguing that the GID overlaps completely with the a1 helix that docks onto nsp3 (FIG.1F), which raises the possibility that nsp3 and GSK-3 may compete in their binding to N. Example 6: R203M and R203K / G204R negatively impact N hyperphosphorylation - 70 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) R203M and R203K / G204R, when experimentally introduced into the genomic background of wildtype SARS-CoV-2, increase virus fitness and transmissibility. The biochemical basis for their positive selection, however, remains uncertain. Here it was examined how they affect N phosphorylation due to their proximity to Ser-206, a site that known to be highly phosphorylated by priming kinases and plays an important role in GSK-3 binding and hyperphosphorylation (FIGs.4A-C). The strep-tagged mutant proteins were expressed in CHIR-99021-treated 293T cells, purified, and characterized by LC-MS / MS (FIGs.5A-5D). Among the six majorly phosphorylated sites, only Ser-206 is significantly affected by the mutations, albeit in opposite ways. R203M greatly reduced Ser-206 phosphorylation, possibly due to the elimination of the upstream (i-3) arginine that is recognized by a basophilic priming kinase (FIG.4A and FIG.4C). Phos-tag gel electrophoresis shows that the primed N*(R203M) has a narrow distribution and migrates closer to the unphosphorylated protein (FIG.4D). Suppression of Ser-206 priming not only renders N(R203M) hyperphosphorylation more sensitive to GSK-3 inhibitor but also makes the dose-response curve steeper (FIGs.4E-4F; FIGs.8A-8B). Furthermore, R203M increases the efficacy of the three priming kinase inhibitors (NCB-0846, dinaciclib, alectinib) (FIG.8C). A combinatorial search has identified conditions where N(R203M) hyperphosphorylation can be completely suppressed using orally available kinase inhibitor drugs at concentrations that are therapeutically achievable (2mM alectinib plus 2mM enzastaurin; FIG.4F). In contrast to R203M, R203K / G204R enhanced Ser-206 phosphorylation (FIGs.4B- 4C). It is possible that introduction of an extra positive charge at the i-2 position makes N a better substrate for the priming kinase, or enables N to be phosphorylated by a new kinase. Intriguingly, increased Ser-206 phosphorylation did not make the protein a better substrate for GSK-3 as previously hypothesized. The observation that hyperphosphorylation became more sensitive to GSK-3 inhibitors suggests that the R203K / G204R double mutation itself could negatively impact GSK-3 binding (FIGs.4E-4F; FIGs.8A-8B). R203K / G204R did not alter the inhibitory activity of priming kinase inhibitors NCB-0846 and dinaciclib but significantly enhanced the efficacy of alectinib (FIG.8C). This is probably because alectinib is the only compound that inhibited Ser-206 phosphorylation, which is expected to exacerbate the negative impact of the double mutation on GSK-3 binding. Example 7: A novel pharmacological strategy to inhibit N hyperphosphorylation - 71 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) The elucidated biochemical mechanism underlying the efficient N hyperphosphorylation by GSK-3, and possibly multiple priming kinases, explains the difficulty in blocking this process by conventional pharmacological means. Although the R203M and R203K / G204R mutations slightly increased the sensitivity to GSK-3 inhibitors (FIGs.4E-4F; FIGs.8A-8B), combining a GSK-3 inhibitor with a priming kinase inhibitor is only successful for the delta mutant at achievable drug concentrations (2mM enzastaurin, 2mM alectinib), but not for the omicron mutant (FIG.4F). It was previously suggested that niclosamide, an anthelmintics drug, could block the binding between N and GSK-3. Although the data do not support this hypothesis, a small inhibitory effect of niclosamide on N hyperphosphorylation was observed (FIG.10A). Unexpectedly, it was discovered that niclosamide greatly enhanced the efficacy and potency of alectinib in blocking N hyperphosphorylation, while demonstrating little synergistic effect with the other two priming kinase inhibitors (NCB-0846, dinaciclib) or GSK-3 inhibitor (CHIR-99021) (FIG.4G). The synergy is unrelated to the inhibition of ALK, the kinase target of alectinib, as several other compounds (except for gilteritinib) that inhibit ALK do not have this activity (FIG.4G). Treating 293T and Calu-3 cells with niclosamide and alectinib reduces GSK-3 protein level in a dose-dependent manner (FIGs.4G-4I), which provides a possible explanation for the decreased phosphorylation of N and endogenous substrate GS. Treating cells expressing the omicron mutant with niclosamide (1mM) and alectinib (2mM) significantly improves the potency of GSK-3 inhibitor enzastaurin (FIG.4J), resulting in almost complete inhibition of N hyperphosphorylation at a drug concentration (2mM) that is therapeutically achievable. Previous observations that niclosamide alone activates autophagy, as well as preliminary characterization (FIGs.10B-10C), suggest that autophagy-mediated protein degradation is likely involved in the mechanism by which combined niclosamide / alectinib treatment reduces GSK-3 protein levels. Niclosamide is being evaluated in 18 COVID-19- related clinical trials, and multiple mechanisms, including autophagy, have been proposed to explain its antiviral activity. A major challenge relates to the drug’s poor pharmacokinetics, although reformulation, intranasal administration, and oral dosing of a prodrug, have shown great promise. Based on results obtained in this study (FIG.4G and FIG.4J), it is argued that co-administration with oral alectinib, or alectinib / enzastaurin combination, should be seriously considered and possibly incorporated in the niclosamide trials to exploit yet another antiviral mechanism (FIGs.1C-1E). It is also noted that the ability of alectinib and gilteritinib to drastically enhance niclosamide’s activity in degrading GSK-3, as well as other cellular - 72 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) proteins (e.g., β-catenin; FIG.4I), could potentially be applied to a wide range of different disease areas such as metabolic, neurological, and neoplastic disorders (FIGs.10D-10E). Sequence Listing SEQ ID NO:1 (S / T)XXX(S / T) SEQ ID NO:2 GFYAEGSR SEQ ID NO:3 GFYAEGSRGGSQASSR SEQ ID NO:4 GGSQASSRSSSRSR SEQ ID NO:5 GGSQASSRSSSRSR SEQ ID NO:6 GGSQASSRSSSRSR SEQ ID NO:7 SRNSSRNSTPGSSR SEQ ID NO:8 NSSRNSTPGSSR SEQ ID NO:9 NSSRNSTPGSSR SEQ ID NO:10 SRNSSRNSTPGSSR SEQ ID NO:11 NSSRNSTPGSSR SEQ ID NO:12 GTSPAR SEQ ID NO:13 NSTPGSSRGTSPAR SEQ ID NO:14 GGSQASSRSSSRSR SEQ ID NO:15 GFYAEGSRGGSQASSR - 73 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) SEQ ID NO:16 GGSQASSRSSSRSR SEQ ID NO:17 GGSQASSRSSSR SEQ ID NO:18 NSSRNSTPGSSRGTSPAR SEQ ID NO:19 SRNSSRNSTPGSSRGTSPAR SEQ ID NO:20 NSSRNSTPGSSRGTSPAR SEQ ID NO:21 SRNSSRNSTPGSSRGTSPAR SEQ ID NO:22 NSTPGSSR SEQ ID NO:23 GTSPARMAGNGGDAALALLLLDR SEQ ID NO:24 GGSQASSRSSSR SEQ ID NO:25 NSSRNSTPGSSR SEQ ID NO:26 SRNSSRNSTPGSSR SEQ ID NO:27 NSTPGSSRGTSPAR SEQ ID NO:28 Homo sapiens GSK-3α (NM_019884.3) MSGGGPSGGGPGGSGRARTSSFAEPGGGGGGGGGGPGGSASGPGGTGGGKASVGAMGGGVGA SSSGGGPGGSGGGGSGGPGAGTSFPPPGVKLGRDSGKVTTVVATLGQGPERSQEVAYTDIKV IGNGSFGVVYQARLAETRELVAIKKVLQDKRFKNRELQIMRKLDHCNIVRLRYFFYSSGEKK DELYLNLVLEYVPETVYRVARHFTKAKLTIPILYVKVYMYQLFRSLAYIHSQGVCHRDIKPQ NLLVDPDTAVLKLCDFGSAKQLVRGEPNVSYICSRYYRAPELIFGATDYTSSIDVWSAGCVL AELLLGQPIFPGDSGVDQLVEIIKVLGTPTREQIREMNPNYTEFKFPQIKAHPWTKVFKSRT PPEAIALCSSLLEYTPSSRLSPLEACAHSFFDELRCLGTQLPNNRPLPPLFNFSAGELSIQP SLNAILIPPHLRSPAGTTTLTPSSQALTETPTSSDWQSTDATPTLTNSS SEQ ID NO:29 Homo sapiens GSK-3β example (NP_001341525.1) MSGRPRTTSFAESCKPVQQPSAFGSMKVSRDKDGSKVTTVVATPGQGPDRPQEVSYTDTKVI GNGSFGVVYQAKLCDSGELVAIKKVLQDKRFKNRELQIMRKLDHCNIVRLRYFFYSSGEKKD EVYLNLVLDYVPETVYRVARHYSRAKQTLPVIYVKLYMYQLFRSLAYIHSFGICHRDIKPQN LLLDPDTAVLKLCDFGSAKQLVRGEPNVSYICSRYYRAPELIFGATDYTSSIDVWSAGCVLA - 74 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) ELLLGQPIFPGDSGVDQLVEIIKVLGTPTREQIREMNPNYTEFKFPQIKAHPWTKVFRPRTP PEAIALCSRLLEYTPTARLTPLEACAHSFFDELRDPNVKLPNGRDTPALFNFTTQDANTGDR GQTNNAASASASNSTMSGGGPSGGGPGGSGRARTSSFAEPGGGGGGGGGGPGGSASGPGGTG GGKASVGAMGGGVGASSSGGGPGGSGGGGSGGPGAGTSFPPPGVKLGRDSGKVTTVVATLGQ GPERSQEVAYTDIKVIGNGSFGVVYQARLAETRELVAIKKVLQDKRFKNRELQIMRKLDHCN IVRLRYFFYSSGEKKDELYLNLVLEYVPETVYRVARHFTKAKLTIPILYVKVYMYQLFRSLA YIHSQGVCHRDIKPQNLLVDPDTAVLKLCDFGSAKQLVRGEPNVSYICSRYYRAPELIFGAT DYTSSIDVWSAGCVLAELLLGQPIFPGDSGVDQLVEIIKVLGTPTREQIREMNPNYTEFKFP QIKAHPWTKVFKSRTPPEAIALCSSLLEYTPSSRLSPLEACAHSFFDELRCLGTQLPNNRPL PPLFNFSAGELSIQPSLNAILIPPHLRSPAGTTTLTPSSQALTETPTSSDWQSTDATPTLTN SS SEQ ID NO:30 Coronavirus N-protein full length (NC_045512.2 28274..29533, GU280_gp10) MSDNGPQNQRNAPRITFGGPSDSTGSNQNGERSGARSKQRRPQGLPNNTASWFTALTQHGKE DLKFPRGQGVPINTNSSPDDQIGYYRRATRRIRGGDGKMKDLSPRWYFYYLGTGPEAGLPYG ANKDGIIWVATEGALNTPKDHIGTRNPANNAAIVLQLPQGTTLPKGFYAEGSRGGSQASSRS SSRSRNSSRNSTPGSSRGTSPARMAGNGGDAALALLLLDRLNQLESKMSGKGQQQQGQTVTK KSAAEASKKPRQKRTATKAYNVTQAFGRRGPEQTQGNFGDQELIRQGTDYKHWPQIAQFAPS ASAFFGMSRIGMEVTPSGTWLTYTGAIKLDDKDPNFKDQVILLNKHIDAYKTFPPTEPKKDK KKKADETQALPQRQKKQQTVTLLPAADLDDFSKQLQQSMSSADSTQA SEQ ID NO:31 HCoV-229E Alphacoronavirus VTVAEEPDSRAPSRSQSRSQSRSRGESKSQSRNSSSDRNH SEQ ID NO:32 HCoV-NL63 Alphacoronavirus EDRSNNSSRASSRSSTRNNSRDSSRSTSRQQSRTRSDSNQ SEQ ID NO:33 Sc-BatCoV 512 Alphacoronavirus TPNNSRANSRSRSRGGQSNSRGNSQNRGDKSRNQSRNRSQ SEQ ID NO:34 Mi-BatCoV HKU8 Alphacoronavirus PSQPNSRSNSRSQSSGGSKSRANSQSRDNSDQQKTPKGST SEQ ID NO:35 SARS-CoV Betacoronavirus GFYAEGSRGGSQASSRSSSRSRGNSRNSTPGSSRGNSPAR SEQ ID NO:36 MERS-CoV Betacoronavirus TGGNSQSSSRASSVSRNSSRSSSQGSRSGNSTRGTSPGPS SEQ ID NO:37 MHV Betacoronavirus VEGSGRSAPASRSGSRSQSRGPNNRARSSSNQRQPASTVK SEQ ID NO:38 IBV Gammacoronavirus NRGRSGRSTAASSAASSRAPSRDGSRGRRSGAEDDLIARA SEQ ID NO:39 SW1 Gammacoronavirus PERGFFIERSRSRSRSNSQADNRSKSRERSQSSDKPRKED SEQ ID NO:40 BuCoV HKU11 Deltacoronavirus DPFNSRGRTLQRGANTRSMSVDARPNNSNQPKKRDQSAPA - 75 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) SEQ ID NO:41 ThCoV HKU12 Deltacoronavirus DPFNTRGRQLERAPGPRSMSMDTRPAANQPRKRDQSAPAA Enumerated Embodiments The following enumerated embodiments are provided, the numbering of which is not to be construed as designating levels of importance: Embodiment 1 provides a method of treating, preventing, and / or ameliorating a disease associated with an overactive or dysregulated Glycogen Synthase Kinase 3 (GSK-3) in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one of Alectinib and Gilteritinib, and a therapeutically effective amount of a compound of Formula (I), or a salt, solvate, prodrug, stereoisomer, or isotopologue thereof: , wherein: R1a, R1b, R1c, R1d, R1e, R2a, R2c, and R2eare each independently selected from the group consisting of: H, halogen, NO2, CN, optionally substituted C1-C6alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C2-C8heteroaryl, ORA, N(RA)(RB), C(=O)RA, C(=O)ORA, C(=O)N(RA)(RB), C(=NRA)N(RA)(RB), S(=O)2ORA, S(=O)2N(RA)(RB), N(RA)C(=O)RB, N(RA)S(=O)2RB, wherein each occurrence of RAand RBis independently selected from the group consisting of optionally substituted C1-C12alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C8 heteroaryl. Embodiment 2 provides a method of treating, preventing, and / or ameliorating coronavirus infection in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one of Alectinib and Gilteritinib, and a therapeutically effective amount of compound of Formula (I), or a salt, solvate, prodrug, stereoisomer, or isotopologue thereof: - 76 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) , wherein: R1a, R1b, R1c, R1d, R1e, independently selected from the group consisting of: H, halogen, NO2, CN, optionally substituted C1-C6 alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C2-C8 heteroaryl, ORA, N(RA)(RB), C(=O)RA, C(=O)ORA, C(=O)N(RA)(RB), C(=NRA)N(RA)(RB), S(=O)2ORA, S(=O)2N(RA)(RB), N(RA)C(=O)RB, N(RA)S(=O)2RB, wherein each occurrence of RAand RBis independently selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C6-C10aryl, and optionally substituted C2-C8 heteroaryl, wherein the compound is not Niclosamide. Embodiment 3 provides a method of treating, preventing, and / or ameliorating tumor neogenesis in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one of Alectinib and Gilteritinib, and a therapeutically effective amount of a compound of Formula (I), or a salt, solvate, prodrug, stereoisomer, or isotopologue thereof: , wherein: R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eare each independently selected from the group consisting of: H, halogen, NO2, CN, optionally substituted C1-C6alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C2-C8heteroaryl, ORA, N(RA)(RB), C(=O)RA, C(=O)ORA, C(=O)N(RA)(RB), C(=NRA)N(RA)(RB), S(=O)2ORA, S(=O)2N(RA)(RB), - 77 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) N(RA)C(=O)RB, N(RA)S(=O)2RB, wherein each occurrence of RAand RBis independently selected from the group consisting of optionally substituted C1-C12alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10aryl, and optionally substituted C2-C8heteroaryl. Embodiment 4 provides a method of treating, preventing, and / or ameliorating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of Niclosamide and a therapeutically effective amount of at least one of Alectinib and Gilteritinib. Embodiment 5 provides a method of treating, preventing, and / or ameliorating a disease associated with an overactive or dysregulated β-catenin in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one of Alectinib and Gilteritinib, and a therapeutically effective amount of a compound of Formula (I), or a salt, solvate, prodrug, stereoisomer, or isotopologue thereof: , wherein: R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eare each independently selected from the group consisting of: H, halogen, NO2, CN, optionally substituted C1-C6 alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C2-C8 heteroaryl, ORA, N(RA)(RB), C(=O)RA, C(=O)ORA, C(=O)N(RA)(RB), C(=NRA)N(RA)(RB), S(=O)2ORA, S(=O)2N(RA)(RB), N(RA)C(=O)RB, N(RA)S(=O)2RB, wherein each occurrence of RAand RBis independently selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C6-C10aryl, and optionally substituted C2-C8 heteroaryl. Embodiment 6 provides the method of Embodiment 1, wherein the GSK-3 is selected from the group consisting of GSK-3α and GSK-3β. Embodiment 7 provides the method of any one of Embodiments 1-6, wherein the - 78 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) compound of Formula (I) or Niclosamide, and Alectinib and / or Gilteritinib are co- administered. Embodiment 8 provides the method of any one of Embodiments 1-7, wherein the compound of Formula (I) or Niclosamide, and Alectinib and / or Gilteritinib are co- formulated. Embodiment 9 provides the method of any one of Embodiments 1 or 6-8, wherein the disease is selected from the group consisting of: tumor neogenesis, bipolar disorder, Alzheimer's disease, a metabolic disorder, diabetes, a chronic inflammatory disease, and myotonic dystrophy. Embodiment 10 provides the method of Embodiment 2, wherein the coronavirus infection is caused by severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), optionally wherein the coronavirus infection is COVID-19. Embodiment 11 provides the method of any one of Embodiments 1-10, wherein the subject is a mammal. Embodiment 12 provides the method of any one of Embodiments 1-11, wherein the subject is a human. Embodiment 13 provides the method of any one of Embodiments 1-12, wherein the molar ratio of a compound of Formula (I) or niclosamide to Alectinib and / or Gilteritinib is about 1:1 or 1:2. Embodiment 14 provides the method of any one of Embodiments 1-13, wherein the method further comprises administering Enzastaurin and / or NCB-0846. Embodiment 15 provides the method of any one of Embodiments 1-3 or 6-14, wherein at least one of the following applies: i) at least one of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H; ii) at least two of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H; iii) at least three of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H; iv) at least four of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H; v) at least five of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H; vi) at least six of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H; vii) at least seven of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H; viii) at least eight of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H; and ix) at least nine of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H. - 79 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) Embodiment 16 provides the method of any one of Embodiments 1-3 or 6-15, wherein at least one of the following applies: i) at least one of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are Cl; ii) at least two of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are Cl; iii) at least three of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are Cl; iv) at least four of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are Cl; and v) at least five of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are Cl. Embodiment 17 provides the method of any one of Embodiments 1-3 or 6-16, wherein R2cis NO2. Embodiment 18 provides the method of any one of Embodiments 1-3 or 6-17, wherein R1ais OH. Embodiment 19 provides the method of any one of Embodiments 1, 3, or 6-18, wherein the compound of Formula (I) is DK-520 (4-chloro-2-((2-chloro-4- nitrophenyl)carbamoyl)phenyl octanoate). Embodiment 20 provides the method of any one of Embodiments 1, 3, or 6-19, wherein the compound of Formula (I) is Niclosamide (5-chloro-N-(2-chloro-4-nitrophenyl)- 2-hydroxybenzamide). Embodiment 21 provides a pharmaceutical composition comprising at least one of Alectinib and Gilteritinib, and a compound of Formula (I), or a salt, solvate, prodrug, stereoisomer, or isotopologue thereof, and one or more pharmaceutical carriers or excipients: , wherein: R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eare each independently selected from the group consisting of: H, halogen, NO2, CN, optionally substituted C1-C6alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C2-C8heteroaryl, ORA, N(RA)(RB), C(=O)RA, C(=O)ORA, C(=O)N(RA)(RB), C(=NRA)N(RA)(RB), S(=O)2ORA, S(=O)2N(RA)(RB), N(RA)C(=O)RB, N(RA)S(=O)2RB, wherein each occurrence of RAand RBis - 80 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) independently selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C8 heteroaryl. Embodiment 22 provides the pharmaceutical composition of Embodiment 21, wherein the molar ratio of the compound of Formula (I) and 9-ethyl-6,6-dimethyl-8-(4- morpholinopiperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Alectinib) and / or 6-ethyl-3-((3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1- yl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide (Gilteritinib) is 1:1 or 1:2 (Formula (I) : Alectinib and / or Gilteritinib). Embodiment 23 provides a method for identifying a combination of compounds which synergistically modulate Glycogen Synthase Kinase 3 (GSK-3) activity, the method comprising contacting a combination of compounds with a cell which constitutively expresses coronavirus nucleocapsid (N) and measuring phosphorylation of the nucleocapsid (N) from the cell. Embodiment 24 provides the method of Embodiment 23, wherein the method further comprises separately contacting each compound of the combination of compounds with a cell which constitutively expresses the coronavirus nucleocapsid (N) and measuring phosphorylation of the nucleocapsid (N) from the cell. Embodiment 25 provides the method of Embodiment 24, wherein the method further comprises comparing (a) nucleocapsid (N) phosphorylation observed by contacting the combination of compounds with the cell which constitutively expresses the coronavirus nucleocapsid (N) and (b) nucleocapsid (N) phosphorylation observed by separately contacting each compound of the combination of compounds with the cell which constitutively expresses the coronavirus nucleocapsid (N). Embodiment 26 provides the method of any one of Embodiments 23-25, wherein the nucleocapsid (N) shares at least 85% sequence homology with SEQ ID NO:30. Embodiment 27 provides the method of any one of Embodiments 23-26, wherein the measuring comprises subjecting a sample of the cell to liquid chromatography-mass spectroscopy (LC-MS). Embodiment 28 provides the method of any one of Embodiments 23-27, wherein each - 81 - 55597352.1 Attorney Docket No.047162-7509WO1(02574) of the compounds is independently a small organic molecule. Embodiment 29 provides the method of any one of Embodiments 23-28, wherein the coronavirus is a variant of SARS CoV-2 selected from the group consisting of Omicron, Delta, Beta, Gamma, and Alpha. Embodiment 30 provides the method of any one of Embodiments 23-29, wherein the cell comprises one or more HEK-293T cells. Embodiment 31 provides the method of any one of Embodiments 27-30, wherein the LC-MS measuring is performed in parallel with at least one other phosphorylation measurement method. Embodiment 32 provides the method of any one of Embodiments 23-31, wherein the method further comprises performing gel electrophoresis of a sample of the cell. Embodiment 33 provides the method of any one of Embodiments 23-32, wherein the method comprises phosphoproteomic analysis of the cell. Embodiment 34 provides the method of any one of Embodiments 23-33, wherein the phosphorylation assay is performed over the course of at least 24 hours, wherein the cell is optionally incubated for at least 24 hours. Embodiment 35 provides the method of any one of Embodiments 23-34, wherein the phosphorylation assay comprises one or more GSK-3 peptides, optionally selected from GSK-3α or GSK-3β, or a variant thereof. The terms and expressions employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the embodiments of the present application. Thus, it should be understood that although the present application describes specific embodiments and optional features, modification and variation of the compositions, methods, and concepts herein disclosed may be resorted to by those of ordinary skill in the art, and that such modifications and variations are considered to be within the scope of embodiments of the present application. - 82 - 55597352.1

Claims

Attorney Docket No.047162-7509WO1(02574) CLAIMS What is claimed is:

1. A method of treating, preventing, and / or ameliorating a disease associated with an overactive or dysregulated Glycogen Synthase Kinase 3 (GSK-3) in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one of Alectinib and Gilteritinib, and a therapeutically effective amount of a compound of Formula (I), or a salt, solvate, prodrug, stereoisomer, or isotopologue thereof: , wherein:R1a, R1b, R1c, R1d, R1e, are independently selected from the group consisting of: H, halogen, NO2, CN, optionally substituted C1-C6 alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C2-C8 heteroaryl, ORA, N(RA)(RB), C(=O)RA, C(=O)ORA, C(=O)N(RA)(RB), C(=NRA)N(RA)(RB), S(=O)2ORA, S(=O)2N(RA)(RB), N(RA)C(=O)RB, N(RA)S(=O)2RB, wherein each occurrence of RAand RBis independently selected from the group consisting of optionally substituted C1-C12alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C8heteroaryl.

2. A method of treating, preventing, and / or ameliorating coronavirus infection in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one of Alectinib and Gilteritinib, and a therapeutically effective amount of compound of Formula (I), or a salt, solvate, prodrug, stereoisomer, or isotopologue thereof: , 55597352.1Attorney Docket No.047162-7509WO1(02574) wherein: R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eare each independently selected from the group consisting of: H, halogen, NO2, CN, optionally substituted C1-C6 alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C2-C8 heteroaryl, ORA, N(RA)(RB), C(=O)RA, C(=O)ORA, C(=O)N(RA)(RB), C(=NRA)N(RA)(RB), S(=O)2ORA, S(=O)2N(RA)(RB), N(RA)C(=O)RB, N(RA)S(=O)2RB, wherein each occurrence of RAand RBis independently selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C6-C10aryl, and optionally substituted C2-C8 heteroaryl, wherein the compound is not Niclosamide.

3. A method of treating, preventing, and / or ameliorating tumor neogenesis in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one of Alectinib and Gilteritinib, and a therapeutically effective amount of a compound of Formula (I), or a salt, solvate, prodrug, stereoisomer, or isotopologue thereof: , wherein:R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eare each independently selected from the group consisting of: H, halogen, NO2, CN, optionally substituted C1-C6alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C2-C8heteroaryl, ORA, N(RA)(RB), C(=O)RA, C(=O)ORA, C(=O)N(RA)(RB), C(=NRA)N(RA)(RB), S(=O)2ORA, S(=O)2N(RA)(RB), N(RA)C(=O)RB, N(RA)S(=O)2RB, wherein each occurrence of RAand RBis independently selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C8 heteroaryl. - 84 - 55597352.1Attorney Docket No.047162-7509WO1(02574) 4. A method of treating, preventing, and / or ameliorating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of Niclosamide and a therapeutically effective amount of at least one of Alectinib and Gilteritinib.

5. A method of treating, preventing, and / or ameliorating a disease associated with an overactive or dysregulated β-catenin in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one of Alectinib and Gilteritinib, and a therapeutically effective amount of a compound of Formula (I), or a salt, solvate, prodrug, stereoisomer, or isotopologue thereof: , wherein:R1a, R1b, R1c, R1d, R1e, are independently selected from the group consisting of: H, halogen, NO2, CN, optionally substituted C1-C6 alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C2-C8 heteroaryl, ORA, N(RA)(RB), C(=O)RA, C(=O)ORA, C(=O)N(RA)(RB), C(=NRA)N(RA)(RB), S(=O)2ORA, S(=O)2N(RA)(RB), N(RA)C(=O)RB, N(RA)S(=O)2RB, wherein each occurrence of RAand RBis independently selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C6-C10aryl, and optionally substituted C2-C8 heteroaryl.

6. The method of claim 1, wherein the GSK-3 is selected from the group consisting of GSK-3α and GSK-3β.

7. The method of any one of claims 1-6, wherein the compound of Formula (I) or Niclosamide, and Alectinib and / or Gilteritinib are co-administered. - 85 - 55597352.1Attorney Docket No.047162-7509WO1(02574) 8. The method of any one of claims 1-7, wherein the compound of Formula (I) or Niclosamide, and Alectinib and / or Gilteritinib are co-formulated.

9. The method of any one of claims 1 or 6-8, wherein the disease is selected from the group consisting of: tumor neogenesis, bipolar disorder, Alzheimer's disease, a metabolic disorder, diabetes, a chronic inflammatory disease, and myotonic dystrophy.

10. The method of claim 2, wherein the coronavirus infection is caused by severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), optionally wherein the coronavirus infection is COVID-19.

11. The method of any one of claims 1-10, wherein the subject is a mammal.

12. The method of any one of claims 1-11, wherein the subject is a human.

13. The method of any one of claims 1-12, wherein the molar ratio of a compound of Formula (I) or niclosamide to Alectinib and / or Gilteritinib is about 1:1 or 1:

2.

14. The method of any one of claims 1-13, wherein the method further comprises administering Enzastaurin and / or NCB-0846.

15. The method of any one of claims 1-3 or 6-14, wherein at least one of the following applies: i) at least one of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H; ii) at least two of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H; iii) at least three of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H; iv) at least four of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H; v) at least five of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H; vi) at least six of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H; vii) at least seven of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H; viii) at least eight of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H; and ix) at least nine of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are H. - 86 - 55597352.1Attorney Docket No.047162-7509WO1(02574) 16. The method of any one of claims 1-3 or 6-15, wherein at least one of the following applies: i) at least one of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are Cl; ii) at least two of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are Cl; iii) at least three of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are Cl; iv) at least four of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are Cl; and v) at least five of R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eand are Cl.

17. The method of any one of claims 1-3 or 6-16, wherein R2cis NO2.

18. The method of any one of claims 1-3 or 6-17, wherein R1ais OH.

19. The method of any one of claims 1, 3, or 6-18, wherein the compound of Formula (I) is DK-520 (4-chloro-2-((2-chloro-4-nitrophenyl)carbamoyl)phenyl octanoate).

20. The method of any one of claims 1, 3, or 6-19, wherein the compound of Formula (I) is Niclosamide (5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide).

21. A pharmaceutical composition comprising at least one of Alectinib and Gilteritinib, and a compound of Formula (I), or a salt, solvate, prodrug, stereoisomer, or isotopologue thereof, and one or more pharmaceutical carriers or excipients: , wherein:R1a, R1b, R1c, R1d, R1e, R2a, R2b, R2c, R2d, and R2eare each independently selected from the group consisting of: H, halogen, NO2, CN, optionally substituted C1-C6alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C2-C8heteroaryl, ORA, N(RA)(RB), C(=O)RA, C(=O)ORA, - 87 - 55597352.1Attorney Docket No.047162-7509WO1(02574) C(=O)N(RA)(RB), C(=NRA)N(RA)(RB), S(=O)2ORA, S(=O)2N(RA)(RB), N(RA)C(=O)RB, N(RA)S(=O)2RB, wherein each occurrence of RAand RBis independently selected from the group consisting of optionally substituted C1-C12 alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C8 heteroaryl.

22. The pharmaceutical composition of claim 21, wherein the molar ratio of the compound of Formula (I) and 9-ethyl-6,6-dimethyl-8-(4-morpholinopiperidin-1-yl)-11-oxo- 6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Alectinib) and / or 6-ethyl-3-((3-methoxy- 4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran-4- yl)amino)pyrazine-2-carboxamide (Gilteritinib) is 1:1 or 1:2 (Formula (I) : Alectinib and / or Gilteritinib).

23. A method for identifying a combination of compounds which synergistically modulate Glycogen Synthase Kinase 3 (GSK-3) activity, the method comprising contacting a combination of compounds with a cell which constitutively expresses coronavirus nucleocapsid (N) and measuring phosphorylation of the nucleocapsid (N) from the cell.

24. The method of claim 23, wherein the method further comprises separately contacting each compound of the combination of compounds with a cell which constitutively expresses the coronavirus nucleocapsid (N) and measuring phosphorylation of the nucleocapsid (N) from the cell.

25. The method of claim 24, wherein the method further comprises comparing (a) nucleocapsid (N) phosphorylation observed by contacting the combination of compounds with the cell which constitutively expresses the coronavirus nucleocapsid (N) and (b) nucleocapsid (N) phosphorylation observed by separately contacting each compound of the combination of compounds with the cell which constitutively expresses the coronavirus nucleocapsid (N).

26. The method of any one of claims 23-25, wherein the nucleocapsid (N) shares at least 85% sequence homology with SEQ ID NO:

30. - 88 - 55597352.1Attorney Docket No.047162-7509WO1(02574) 27. The method of any one of claims 23-26, wherein the measuring comprises subjecting a sample of the cell to liquid chromatography-mass spectroscopy (LC-MS).

28. The method of any one of claims 23-27, wherein each of the compounds is independently a small organic molecule.

29. The method of any one of claims 23-28, wherein the coronavirus is a variant of SARS CoV-2 selected from the group consisting of Omicron, Delta, Beta, Gamma, and Alpha.

30. The method of any one of claims 23-29, wherein the cell comprises one or more HEK-293T cells.

31. The method of any one of claims 27-30, wherein the LC-MS measuring is performed in parallel with at least one other phosphorylation measurement method.

32. The method of any one of claims 23-31, wherein the method further comprises performing gel electrophoresis of a sample of the cell.

33. The method of any one of claims 23-32, wherein the method comprises phosphoproteomic analysis of the cell.

34. The method of any one of claims 23-33, wherein the phosphorylation assay is performed over the course of at least 24 hours, wherein the cell is optionally incubated for at least 24 hours.

35. The method of any one of claims 23-34, wherein the phosphorylation assay comprises one or more GSK-3 peptides, optionally selected from GSK-3α or GSK-3β, or a variant thereof. - 89 - 55597352.1

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