Methods and materials for treating cancer

Abstract

This document relates to methods and materials for treating cancer. For example, this document provides methods and materials for using one or more signal transducer and activator of transcription 3 (STAT3) polypeptide inhibitors to treat a mammal (e.g., a human) having cancer (e.g., a brain cancer such as a glioma).

Description

[0001] METHODS AND MATERIALS FOR TREATING CANCER

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Patent Application Serial No. 63 / 624,033, filed on January 23, 2024. The disclosure of the prior application is considered part of, and is incorporated by reference in, the disclosure of this application.

[0004] STATEMENT REGARDING FEDERAL FUNDING

[0005] This invention was made with government support under NS092891 awarded by the National Institutes of Health. The government has certain rights in the invention.

[0006] TECHNICAL FIELD

[0007] This document relates to methods and materials for treating cancer. For example, this document provides methods and materials for using one or more signal transducer and activator of transcription 3 (STAT3) polypeptide inhibitors to treat a mammal (e.g., a human) having cancer (e g., a brain cancer such as a glioma).

[0008] BACKGROUND

[0009] Gliomas comprise about 80 percent of all malignant brain tumors (Goodenberger et al., Cancer Genetics. 205(12):613-21 (2012)). Diffuse intrinsic pontine glioma (DIPG), also referred to as diffuse midline glioma (DMG), is a form of glioma that primarily affects children (e.g., pediatric DIPG), and has a median survival that is under 12 months (Kebudi et al., Paediatric Drugs. 15(5):351-62 (2013). Compared to other types of rare brain tumors, DMG is most prevalent among children (Truitt et al., J. Neurooncol., 144(l):53-63 (2019)) and is uniformly lethal as no effective therapy has been elucidated. The overall survival of all children diagnosed with DMG remains less than 1 year with radiotherapy as the only standard of care (Rechberger et al., Childs Nerv. Syst., 36(l):39-46 (2020)). Surgery to attempt tumor removal is not possible for diffuse pontine gliomas due to the anatomical location and the diffuse pattern growth where the tumors invade diffusely throughout the brain stem, growing between normal nerve cells, such that aggressive surgery would cause severe damage to neural structures vital for arm and leg movement, eye movement, swallowing, breathing, and even consciousness.

[0010] SUMMARY

[0011] This document provides methods and materials for treating cancer. For example, this document provides compounds (e.g., pyrazole compounds) having the structure of Formula (I) as well as methods and materials for using one or more compounds having the structure of Formula (I). In some cases, one or more compounds having the structure of Formula (I) can be used to inhibit a STAT3 polypeptide. In some cases, one or more compounds having the structure of Formula (I) can be administered to a mammal (e.g., a human) having cancer (e.g., a brain cancer such as a glioma) to treat that mammal. As demonstrated herein, one or more compounds having the structure of Formula (I) can inhibit a STAT3 polypeptide and can be used to treat cancer (e.g., a brain cancer such as a glioma) within a mammal (e.g., a human).

[0012] In general, one aspect of this document features compounds having a structure of Formula (I): where R1is S(O)2N=C(Rlb)N(Rla)2 or C(O)ORlc; where each R1a is independently H or Ci- C6alkyl, Rlbis H or C1-C6alkyl, and R1cis H or C1-C6alkyl; where R2is C6-C10aryl optionally substituted with halogen, C1-C6alkoxy, or C1-C6alkyl; where R3is C6-C10aryl optionally substituted with halogen, C1-C6alkoxy, or C1-C6alkyl; and where one of R2or R3is C1-C6alkyl and one of R2or R3is C6-C10aryl optionally substituted with halogen, C1-C6alkoxy, or C1-C6alkyl. The compound can have the structure:

[0013] The compound can have the structure:

[0014] In another aspect, this document features compounds having a structure of Formula

[0015] (I): where R1is S(O)2N(Rla)2; where each Rlais independently H or C1-C6alkyl; where R2is Cs- Cio aryl substituted with Cl, C1-C6alkoxy, or C1-C6alkyl; where R3is C6-C10aryl substituted with Cl, C1-C6alkoxy, or C1-C6alkyl; and where one of R2or R3is C1-C6alkyl and one of R2or R3is C6-C10aryl substituted with Cl, C1-C6alkoxy, or C1-C6alkyl. The compound can have the structure:

[0016] In another aspect, this document features pharmaceutical compositions including a compound having a structure of Formula (I): where R1is S(O)iN=C(Rlb)N(Rla)2 or C(O)ORlc; where each Rlais independently H or Ci- C6alkyl, R,bis H or C1-C6alkyl, and R,cis H or C1-C6alkyl; where R2is C6-C10aryl optionally substituted with halogen, C1-C6alkoxy, or C1-C6alkyl; where R3is C6-C10aryl optionally substituted with halogen, C1-C6alkoxy, or C1-C6alkyl; and where one of R2or R3is C1-C6alkyl and one of R2or R3is C6-C10aryl optionally substituted with halogen, C1-C6alkoxy, or C1-C6alkyl or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent. The compound can have the structure:

[0017] The compound can have the structure:

[0018] In another aspect, this document features pharmaceutical compositions including a compound having a structure of Formula (I): where R1is S(O)2N(Rla)2; where each Rlais independently H or C1-C6alkyl; where R2is C6- Cio aryl substituted with Cl, C1-C6alkoxy, or C1-C6alkyl; where R3is C6-C10aryl substituted with Cl, C1-C6alkoxy, or C1-C6alkyl; and where one of R2or R3is C1-C6alkyl and one of R2 or R3is C6-C10aryl substituted with Cl, C1-C6alkoxy, or C1-C6alkyl or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent. The compound can have the structure:

[0019] In another aspect, this document features methods for treating a mammal having a cancer. The methods can include, or consist essentially of, administering a compound having a structure of Formula (I): where R1is S(O)2N=C(Rlb)N(Rla)2 or C(O)ORlc; where each Rlais independently H or Ci- C6alkyl, Rlbis H or C1-C6alkyl, and Rlcis H or C1-C6alkyl; where R2is C6-C10aryl optionally substituted with halogen, C1-C6alkoxy, or C1-C6alkyl; where R3is C6-C10aryl optionally substituted with halogen, C1-C6alkoxy, or C1-C6alkyl; and where one of R2or R3is C1-C6alkyl and one of R2or R3is C6-C10aryl optionally substituted with halogen, C1-C6alkoxy, or C1-C6alkyl or a pharmaceutical composition including the compound to a mammal having cancer. The compound can have the structure:

[0020] The compound can have the structure:

[0021] The mammal can be a human. The human can be less than 21 years of age. The cancer can be a glioma. The glioma can be a diffuse intrinsic pontine glioma. The cancer can include one or more cancer cells having a genome including K27M substitution in a histone H3 polypeptide. The mammal can have been identified as having said cancer. The method also can include subjecting said mammal to radiation therapy.

[0022] In another aspect, this document features methods for treating a mammal having a cancer. The methods can include, or consist essentially of, administering a compound having a structure of Formula (I): where R1is S(O)2N(R1a)2; where each Rlais independently H or C1-C6alkyl; where R2is C6- Cio aryl substituted with Cl, C1-C6alkoxy, or C1-C6alkyl; where R3is C6-C10aryl substituted with Cl, C1-C6alkoxy, or C1-C6alkyl; and where one of R2or R3is C1-C6alkyl and one of R2or R3is C6-Cio aryl substituted with Cl, C1-C6alkoxy, or C1-C6alkyl or a pharmaceutical composition including the compound to a mammal having cancer. The compound can have the structure:

[0023] The mammal can be a human. The human can be less than 21 years of age. The cancer can be a glioma. The glioma can be a diffuse intrinsic pontine glioma. The cancer can include one or more cancer cells having a genome including K27M substitution in a histone H3 polypeptide. The mammal can have been identified as having said cancer. The method also can include subjecting said mammal to radiation therapy.

[0024] In another aspect, this document features methods for inhibiting a STAT3 polypeptide in a mammal. The methods can include, or consist essentially of, administering a compound having a structure of Formula (I): where R1is S(O)2N=C(Rlb)N(Rla)2 or C(O)ORlc; where each Rlais independently H or Ci- C6alkyl, Rlbis H or C1-C6alkyl, and Rlcis H or C1-C6alkyl; where R2is C6-C10aryl optionally substituted with halogen, C1-C6alkoxy, or C1-C6alkyl; where R3is C6-C10aryl optionally substituted with halogen, C1-C6alkoxy, or C1-C6alkyl; and where one of R2or R3is C1-C6alkyl and one of R2or R3is C6-C10aryl optionally substituted with halogen, C1-C6alkoxy, or C1-C6alkyl or a pharmaceutical composition including the compound to a mammal. The compound can have the structure:

[0025] The compound can have the structure:

[0026] The mammal can be a human. The human can be less than 21 years of age. The mammal can have a cancer. The cancer can be a glioma. The glioma can be a diffuse intrinsic pontine glioma. The cancer can include one or more cancer cells having a genome including K27M substitution in a histone H3 polypeptide.

[0027] In another aspect, this document features methods for inhibiting a STAT3 polypeptide in a mammal. The methods can include, or consist essentially of, administering a compound having a structure of Formula (I): where R1is S(O)2N(Rla)2; where each Rlais independently H or C1-C6alkyl; where R2is C6,- Cio aryl substituted with Cl, C1-C6alkoxy, or C1-C6alkyl; where R3is C6-C10 aryl substituted with C1, C1-C6alkoxy, or C1-C6alkyl; and where one of R2or R3is C1-C6alkyl and one of R2or R3is C6-C10aryl substituted with Cl, C1-C6alkoxy, or C1-C6alkyl or a pharmaceutical composition including the compound to a mammal. The compound can have the structure:

[0028] The mammal can be a human. The human can be less than 21 years of age. The mammal can have a cancer. The cancer can be a glioma. The glioma can be a diffuse intrinsic pontine glioma. The cancer can include one or more cancer cells having a genome including K27M substitution in a histone H3 polypeptide.

[0029] In another aspect, this document features uses of a compound having a structure of Formula (I): where R1is S(O)2N=C(Rlb)N(Rla)2 or C(O)ORlc; where each Rlais independently H or Ci- C6alkyl, Rlbis H or C1-C6alkyl, and Rlcis H or C1-C6alkyl; where R2is C6-C10aryl optionally substituted with halogen, C1-C6alkoxy, or C1-C6alkyl; where R3is C6-C10aryl optionally substituted with halogen, C1-C6alkoxy, or C1-C6alkyl; and where one of R2or R3is C1-C6alkyl and one of R2or R3is Cs-Cio aryl optionally substituted with halogen, C1-C6alkoxy, or C1-C6alkyl to treat a mammal having a cancer. The compound can have the structure:

[0030] The compound can have the structure:

[0031] In another aspect, this document features uses of a compound having a structure of Formula (I): where R1is S(O)aN(Rla)2; where each Rlais independently H or C1-C6alkyl; where R2is C6- Cio aryl substituted with Cl, C1-C6alkoxy, or C1-C6alkyl; where R3is C6-C10aryl substituted with Cl, C1-C6alkoxy, or C1-C6alkyl; and where one of R2or R3is C1-C6alkyl and one of R2or R3is C6-C10aryl substituted with Cl, C1-C6alkoxy, or C1-C6alkyl to treat a mammal having a cancer. The compound can have the structure:

[0032]

[0033] In another aspect, this document features a compound having a structure of Formula

[0034] (I): where R1is S(O)iN=C(Rlb)N(R1a)2 or C(O)OR1C; where each Rlais independently H or Ci- C6alkyl, Rlbis H or C1-C6alkyl, and Rleis H or C1-C6alkyl; where R2is C6-C10aryl optionally substituted with halogen, C1-C6alkoxy, or C1-C6alkyl; where R3is C6-C10aryl optionally substituted with halogen, C1-C6alkoxy, or C1-C6alkyl; and where one of R2or R3is C1-C6alkyl and one of R2or R3is C6-C10aryl optionally substituted with halogen, C1-C6alkoxy, or C1-C6alkyl for use in the preparation of a medicament to treat a cancer. The compound can have the structure:

[0035] The compound can have the structure:

[0036] In another aspect, this document features a compound having a structure of Formula

[0037] (I): where R1is S(O)2N(Rla)2; where each Rlais independently H or C1-C6alkyl; where R2is C6- Cio aryl substituted with Cl, C1-C6alkoxy, or C1-C6alkyl; where R3is C6-C10aryl substituted with Cl, C1-C6alkoxy, or C1-C6alkyl; and where one of R2or R3is C1-C6alkyl and one of R2or R3is C6-C10aryl substituted with Cl, C1-C6alkoxy, or C1-C6alkyl for use in the preparation of a medicament to treat a cancer. The compound can have the structure:

[0038] In another aspect, this document features a compound having a structure of Formula

[0039] (I): where R1is S(O)2N=C(Rlb)N(Rla)2 or C(O)ORlc; where each Rlais independently H or Ci- C6alkyl, Rlbis H or C1-C6alkyl, and Rleis H or C1-C6alkyl; where R2is C6-C10aryl optionally substituted with halogen, C1-C6alkoxy, or C1-C6alkyl; where R3is C6-C10aryl optionally substituted with halogen, C1-C6alkoxy, or C1-C6alkyl; and where one of R2or R3is C1-C6alkyl and one of R2or R3is C6-C10aryl optionally substituted with halogen, C1-C6alkoxy, or C1-C6alkyl for use in the treatment of a cancer. The compound can have the structure:

[0040] The compound can have the structure:

[0041] In another aspect, this document features a compound having a structure of Formula

[0042] (I): where R1is S(O)2N(Rla)2; where each Rlais independently H or C1-C6alkyl; where R2is Cs- Cio aryl substituted with Cl, C1-C6alkoxy, or C1-C6alkyl; where R3is C6-C10aryl substituted with Cl, C1-C6alkoxy, or C1-C6alkyl; and where one of R2or R3is C1-C6alkyl and one of R2or R3is C6-C10aryl substituted with Cl, C1-C6alkoxy, or C1-C6alkyl for use in the treatment of a cancer. The compound can have the structure:

[0043] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0044] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

[0045] BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figures 1A-1C show exemplary structures of Formula (I). Figure 1A shows the structure of Br-Leu (Lo-Rf, also referred to as compound la). Figure IB shows the structure of Br-Leu-Blue (Hi-Rf, also referred to as compound lb). Figure 1C shows the structure of Br-Leu-Blue-COOH (Hi-Rf, also referred to as compound 4b).

[0047] Figures 2A-2E shows images of immunoblot analysis STAT3 inhibition. Figure 2A shows STAT3 inhibition for compounds la, lb, 2a, 2b, 3a, 3b, 4a, 4b, 5a, and 5b. Figure 2B shows STAT3 inhibition for compounds 6a, 6b, 7a, and 7b. Figure 2C shows STAT3 inhibition for compounds 8a, 8b, 9a, and 9b. Figure 2D shows STAT3 inhibition for compounds 10a, 10b, 11a, 11b, 12a, 12b, 13a, and 13b. Figure 2E shows STAT3 inhibition for compounds 14a, 14b, 15a, 15b, 16a, 16b, 17a, and 17b.

[0048] Figures 3A-3E show cell viability in the presence of compounds la (Figure 3 A), lb (Figure 3B), 3b (Figure 3C), 4b (Figure 3D), and 8a (Figure 3E) in normal cells and in tumor cell lines. Normal cell line: normal human astrocytes (NHA); Cancer cell lines: DIPG cell lines: DIPG XVII, DID 22, DIPG IV, PED 17.

[0049] Figure 4 shows an immunoblot analysis of STAT3 inhibition in the presence of compounds la, lb, 3b, 4b, and 8a as compared to known STAT3 inhibitor (WP1066) or JAK1 / 2 inhibitor (ruxolitinib).

[0050] Figures 5A-5B show the binding affinity of compounds lb and 4b to STAT3 as measured using isothermal titration calorimetry (ITC). Figure 5A shows a graph of the integrated heat peak presented in a Wiseman plot against the molar ratio of the drug, and the binding signature of compound lb. Figure 5B shows a graph of the integrated heat peak presented in a Wiseman plot against the molar ratio of the drug, and the binding signature of compound 4b.

[0051] Figures 6A-6D show that the effects of exemplary structures of Formula (I) are STAT3 dependent. Figure 6A shows a Pearson correlation of compounds la, lb, 3b, 4b, and 8a plotted of percent STAT3 activation inhibition against ICso tested DIPG XVII. Figure 6B is a graph showing that CRISPR knockout of STAT3 in SF8628 (DIPG cell line) leads to loss of potency of compound 4b with a right shift of cell viability. Figure 6C is a graph showing that CRISPR knockout of STAT3 in SF8628 (DIPG cell line) resulted in increased in viability when treated with compound 4b. ICso values were measured using one-way ANOVA, Tukey post-hoc test. Figure 6D is an immunoblot confirming CRISPR knockout of STAT3.

[0052] Figure 7 is a survival curve of mice that were implanted orthotopically with DIPG XVII in the pons and then subsequently treated with compound 4b (150 μM). N=8-9 mice per group.

[0053] Figure 8 shows solubility of compounds la, lb, and 4b.

[0054] Figure 9 shows stability of compound 4b.

[0055] Figure 10 shows that common STAT3 inhibitors WP1066 and Stattic following 24 hour treatment resulted in biological feedback to further potentiate STAT3 activation rather than inhibition.

[0056] Figures 11 A-l IB show a comparison of STAT3 activity in correlation to cell viability in the presence of WP1066 (Figure 11 A) or compound 4b (Figure 1 IB).

[0057] Figures 12A-12B show potency of WP1066. Figure 12A shows that CRISPR knockout of STAT3 in SF8628 cells had no impact on cell viability when treated with WP1066. Figure 12B shows that CRISPR knockout of STAT3 in SF8628 cells resulted in no change in ICso when treated with WP1066. ICso values were measured using one-way ANOVA, Tukey post-hoc test.

[0058] Figures 13A-13C shows pharmacokinetics of compound 4b. Figure 13A shows the percent of compound 4b that remained in the brain tissue following an acute CED infusion of 150 μM of compound 4b. Figure 13B shows a tissue distribution of compound 4b after a single dose of oral gavage (40 mg / kg). Figure 13C shows a tissue to plasma ratio of the amount of compound 4b remaining 1 hour post oral gavage.

[0059] Figure 14 shows that compound 4b provided better protection to JAK-STAT pathway proteins against heat degradation than ruxolitinib.

[0060] Figure 15 shows that compound 4b inhibited phosphorylation of JAK1, JAK2, TYK2 and STAT3 during the IL6-induced pathway activation, suggesting that compound 4b can be used as a pan inhibitor of JAK-STAT pathway.

[0061] Figures 16A-16D show that compound 4b provided prolonged inhibition of STAT pathway during IL6- or IFN-y-induced activation. Figures 16A and 16B) Following 24-hour serum starvation dBTl 14 (GBM cells) were pre-treated with the indicated conceitrations of 4b, WP1066, or ruxolitinib for 1 hour followed by acute induction with either IL16 or IFN-y for 15 minutes. The cells were subsequently harvested and subjected immunoblotting to analyze the level of phosphorylated on the indicated targets. Figures 16C and 16D) dBTl 14 cells were treated (in 10% FBS containing media) concurrently with the indicated concentrations of 4b, WP1066, or ruxolitinib along with either IL6 or IFN-y for 24 hours. The cells were subsequently harvested and subjected immunoblotting to analyze the level of protein expression on the indicated targets. Blots are representative of 3 independent experiments.

[0062] DETAILED DESCRIPTION

[0063] This document provides compounds (e.g., pyrazole compounds) and methods and materials for using compounds to treat mammals (e.g., humans) having cancer (e.g., a brain cancer such as a glioma). For example, this document provides compounds having the structure of Formula (I), or a pharmaceutically acceptable salt thereof: where R1can be S(O)2N(Rla)2, S(O)2N=C(Rlb)N(Rla)2, or C(O)ORlc; each Rlais independently H or C1-C6alkyl, Rlbis H or C1-C6alkyl, and Rlcis H or C1-C6alkyl; R2is C6-C10aryl optionally substituted with halogen, C1-C6alkoxy, or C1-C6alkyl; and R3is C6- Cio aryl optionally substituted with halogen, C1-C6alkoxy, or C1-C6alkyl; provided that one of R2or R3is C1-C6alkyl and one of R2or R3is C6-C10aryl optionally substituted with halogen, C1-C6alkoxy, ,or C1-C6alkyl; and provided that if R1is S(O)aN(Rla)2, then one of R2or R3is C1-C6alkyl and one of R2or R3is C6-C10aryl substituted with Cl, C1-C6alkoxy, or C1-C6alkyl.

[0064] In some cases where the R1present in a compound having the structure of Formula (I) is S(O)zN(Rla)2 or S(O)zN=C(Rlb)N(Rla)2, each Rlacan independently be a H or can be a Ci- Ce alkyl. In some cases, one Rlacan be a H and one Rlacan be a C1-C6alkyl. For example, one Rlacan be a H and one Rlacan be a methyl. In some cases, each Rlacan be a H. In some cases, each Rlacan be a C1-C6alkyl. For example, each Rlacan be a methyl.

[0065] In some cases where the R1present in a compound having the structure of Formula (I) is S(O)2N=C(Rlb)N(Rla)2, Rlbcan be a H or can be a C1-C6alkyl. In some cases, Rlbcan be a H. In some cases, Rlbcan be a C1-C6alkyl. For example, Rlbcan be a methyl.

[0066] In some cases where the R1present in a compound having the structure of Formula (I) is C(O)ORlc, the Rlccan be a H or can be a C1-C6alkyl. For example, Rlccan be a H. For example, Rlccan be a C1-C6alkyl. For example, Rlccan be a methyl.

[0067] In some cases where the R2present in a compound having the structure of Formula (I) is a Cs-Cio aryl optionally substituted with halogen, R2can be any appropriate Cs-Cio aryl optionally substituted with halogen. The halogen can be any appropriate halogen. For example, the halogen can be a fluorine, a chlorine, a bromine, or an iodine.

[0068] In some cases where the R2present in a compound having the structure of Formula (I) is a C6-C10aryl optionally substituted with C1-C6alkoxy, R2can be any appropriate C6-C10aryl optionally substituted with Ci-Gs alkoxy. For example, R2can be substituted with methoxy. For example, R2can be substituted with ethoxy. For example, R2can be substituted with a propoxy. For example, R2can be substituted with an isopropoxy. For example, R2can be substituted with a butoxy. For example, R2can be substituted with a pentoxy. For example, R2can be substituted with an isopentoxy. In some cases where the R2present in a compound having the structure of Formula (I) is a C1-C6alkyl, R2can be any appropriate C1-C6alkyl. For example, R2can be a methyl. For example, R2can be ethyl. For example, R2can be a propyl. For example, R2can be an isopropyl. For example, R2can be a butyl. For example, R2can be a pentyl. For example, R2can be an isopentyl.

[0069] In some cases, R2can be a phenyl substituted with halogen.

[0070] In cases where the R3present in a compound having the structure of Formula (I) is a C6-C10aryl optionally substituted with halogen, R3can be any appropriate C6-C10aryl optionally substituted with halogen. The halogen can be any appropriate halogen. For example, the halogen can be a fluorine, a chlorine, a bromine, or an iodine.

[0071] In some cases where the R3present in a compound having the structure of Formula (I) is a C6-C10aryl optionally substituted with C1-C6alkoxy, R3can be any appropriate C6-C10aryl optionally substituted with C1-C6alkoxy. For example, R3can be substituted with methoxy. For example, R3can be substituted with ethoxy. For example, R3can be substituted with a propoxy. For example, R3can be substituted with an isopropoxy. For example, R3can be substituted with a butoxy. For example, R3can be substituted with a pentoxy. For example, R3can be substituted with an isopentoxy.

[0072] In some cases where the R3present in a compound having the structure of Formula (I) is a C1-C6alkyl, R3can be any appropriate C1-C6alkyl. For example, R3can be a methyl. For example, R3can be an ethyl. For example, R3can be a propyl. For example, R3can be an isopropyl. For example, R3can be a butyl. For example, R3can be a pentyl. For example, R3can be an isopentyl.

[0073] In some cases, R3can be a phenyl substituted with halogen.

[0074] In some cases, a compound provided herein can have the structure of Formula (1) where R1is S(O)2N=C(Rlb)N(Rla)2;R2is C1-C6alkyl; and R3is C6-C10aryl optionally substituted with halogen.

[0075] In some cases, a compound provided herein can have the structure of Formula (I) where R1is C(O)ORlc;R2is C1-C6alkyl; and R3is C6-C10aryl optionally substituted with halogen. In some cases, a compound provided herein can have the structure of Formula (I) where R1is C(O)ORlc;R2is C6-C10aryl optionally substituted with halogen; and R3is Ci-Q alkyl. For example, a compound provided herein can be a compound having the following structure, or a pharmaceutically acceptable salt thereof, also referred to as Br-Leu-Blue- COOH (Hi-Rf):

[0076] In some cases, a compound provided herein can have the structure of Formula (I) where R1is S(O)2N=C(Rlb)N(Rla)2;R2is C6-C10aryl optionally substituted with halogen; and R3is C1-C6alkyl. For example, a compound provided herein can be a compound having the following structure, or a pharmaceutically acceptable salt thereof, also referred to as Br-Leu- Blue-NSFA (Hi-Rf):

[0077] In some cases, a compound provided herein can have the structure of Formula (I) where R1is S(O)2N(Rla)2;R2is C1-C6alkyl; and R3is C6-C10aryl optionally substituted with halogen. For example, a compound provided herein can be a compound having the following structure, or a pharmaceutically acceptable salt thereof, also referred to as Cl-Leu (Lo-Rf):

[0078]

[0079] In some cases, a compound of Formula (I) is not a compound disclosed in International Patent Application Publication No. WO 2013 / 187965. For example, in some cases, a compound of Formula (I) is not 4-(5-(4-bromophenyl)-3-isopentyl-lH-pyrazol-l- yl)benzenesulfonamide. For example, in some cases, a compound of Formula (I) is not 4-(3- (4-bromophenyl)-5-isopentyl-lH-pyrazol-l-yl)benzenesulfonamide.

[0080] In some cases, a compound provided herein (e.g., a compound having the structure of Formula (I)) can be in the form of a salt (e.g., pharmaceutically acceptable salt). A salt of a compound provided herein can be formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. When a compound having the structure of Formula (I) is in the form of a salt, the salt can include any appropriate acid (e.g., an organic acid or an inorganic acid). Examples of acids that can be used to form a pharmaceutically acceptable salt of a compound described herein include, without limitation, inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic add, oxalic acid, para-bromophenylsulfonic add, carbonic add, succinic acid, citric add, benzoic acid and acetic add, as well as related inorganic and organic adds. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne- 1,4- dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, 0-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, naphthalene-2- sulfonate, mandelate and other salts. In some cases, pharmaceutically acceptable acid addition salts can be used including, without limitation, those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid. Examples of bases that can be used to form a pharmaceutically acceptable salt of a compound described herein include, without limitation, hydroxides of alkali metals, including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(Cl-C6)-alkylamine), such as N,N- dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like. In some cases, a compound described herein, or a pharmaceutically acceptable salt thereof, can be substantially isolated.

[0081] At various places herein, substituents of compounds described herein are described in groups or in ranges. It is specifically intended that this document include and describe each and every individual member or subcombination of the members of such groups and ranges. For example, the term “C1-C6alkyl” is specifically intended to individually disclose methyl, ethyl, C3alkyl, C4alkyl, C5alkyl, and C6alkyl.

[0082] At various places herein, various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency. For example, the term “a pyridine ring" or “pyridinyl” may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

[0083] It is further appreciated that certain features herein, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features herein which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0084] As used herein, the phrase “optionally substituted" means unsubstituted or substituted. The substituents are independently selected, and substitution may be at any chemically accessible position. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. It is to be understood that substitution at a given atom is limited by valency.

[0085] Throughout the definitions, the term “Cn-m" indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C1-4, C1-4, and the like.

[0086] As used herein, the term “Cn-malkyl”, used alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons. Examples of alkyl moieties include, without limitation, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-l -butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

[0087] The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0088] In some cases, a compound provided herein (e.g., a compound having the structure of Formula (I)) can inhibit activation (e.g., phosphorylation) of a STAT3 polypeptide. For example, a compound provided herein (e.g., a compound having the structure of Formula (I)) can be administered to a mammal (e.g., a human such as a human having cancer such as a brain cancer (e.g., a glioma)) to inhibit activation (e.g., phosphorylation) of a STAT3 polypeptide within the mammal. In some cases, a compound provided herein (e.g., a compound having the structure of Formula (I)) can inhibit a STAT3 polypeptide for any appropriate amount of time. For example, a compound provided herein (e.g., a compound having the structure of Formula (I)) can be administered to a mammal (e.g., a human such as a human cancer such as a brain cancer (e.g., a glioma)) to inhibit a STAT3 polypeptide within a cell (e.g., a cell within the mammal) for at least 24 hours following the administration.

[0089] In some cases, a compound provided herein (e.g., a compound having the structure of Formula (I)) can have any appropriate half-maximal inhibitory concentration (ICso). For example, a compound provided herein (e.g., a compound having the structure of Formula (I)) can have an ICSO of less than about 10 μM (e.g., in cancer cells). For example, a compound provided herein (e.g., a compound having the structure of Formula (I)) can have an ICso (e.g., in cancer cells) of from about 1.5 μM to about 10 μM (e.g., from about 1.5 μM to about 8 μM, from about 1.5 μM to about 5 μM, from about 1.5 μM to about 3 μM, from about 1.5 μM to about 10 μM, from about 2 μM to about 10 μM, from about 5 μM to about 10 μM, from about 7 μM to about 10 μM, from about 2 μM to about 8 μM, from about 3 μM to about 7 μM, from about 4 μM to about 6 μM, from about 2 μM to about 5 μM, from about 3 μM to about 6 μM, from about 4 μM to about 7 μM, from about 5 μM to about 8 μM, or from about 6 μM to about 9 μM).

[0090] In some cases, a compound provided herein (e.g., a compound having the structure of Formula (I)) can have any appropriate therapeutic index (e.g., a ratio of the ICso in healthy cells to the ICso in cancer cells). For example, a compound provided herein (e.g., a compound having the structure of Formula (I)) can have a therapeutic index of greater than about 0.2. For example, a compound provided herein (e.g., a compound having the structure of Formula (I)) can have a therapeutic index of from about 0.2 to about 10 (e.g., from about 0.2 to about 7, from about 0.2 to about 5, from about 0.2 to about 3, from about 0.2 to about 1, from about 1 to about 10, from about 3 to about 10, from about 5 to about 10, from about 8 to about 10, from about 1 to about 8, from about 3 to about 5, from about 1 to about 5, from about 2 to about 6, from about 3 to about 7, from about 4 to about 8, or from about 5 to about 9).

[0091] In some cases, a compound provided herein (e.g., a compound having the structure of Formula (I)) can have any appropriate solubility. For example, a compound provided herein (e.g., a compound having the structure of Formula (I)) can have a solubility of greater than about 2 μM. For example, a compound provided herein (e.g., a compound having the structure of Formula (I)) can have a solubility of from about 2 μM to about 175 μM (e.g., from about 2 μM to about 150 μM, from about 2 μM to about 125 μM, from about 2 μM to about 100 μM, from about 2 μM to about 75 μM, from about 2 μM to about 50 μM, from about 2 μM to about 25 μM, from about 2 μM to about 10 μM, from about 10 μM to about 175 μM, from about 25 μM to about 175 μM, from about 50 μM to about 175 μM, from about 75 μM to about 175 μM, from about 100 μM to about 175 μM, from about 125 μM to about 175 μM, from about 150 μM to about 175 μM, from about 10 μM to about 150 μM, from about 25 μM to about 125 μM, from about 50 μM to about 100 μM, from about 25 μM to about 50 μM, from about 50 μM to about 75 μM, from about 75 μM to about 100 μM, from about 100 μM to about 125 μM, or from about 125 μM to about 150 μM).

[0092] In some cases, a compound provided herein (e.g., a compound having the structure of Formula (I)) can have cross a blood-brain barrier. For example, a compound provided herein (e.g., a compound having the structure of Formula (I)) can be administered to a mammal (e.g., a human such as a human having cancer such as a brain cancer (e.g., a glioma)) and can cross the blood-brain barrier within the mammal.

[0093] In some cases, one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)) can be formulated into a composition (e.g., a pharmaceutically acceptable composition) for administration to a mammal (e.g., a human) having cancer (e.g., a brain cancer such as a glioma). For example, one or more compounds having the structure of Formula (I) can be formulated together with one or more pharmaceutically acceptable carriers (additives), excipients, and / or diluents. Examples of pharmaceutically acceptable carriers, excipients, and diluents that can be used in a composition described herein include, without limitation, cyclodextrins (e.g., betacyclodextrins such as KLEPTOSE®), dimethylsulfoxide (DMSO), sucrose, lactose, starch (e g., starch glycolate), cellulose, cellulose derivatives (e g., modified celluloses such as microcrystalline cellulose, and cellulose ethers like hydroxypropyl cellulose (HPC) and cellulose ether hydroxypropyl methylcellulose (HPMC)), xylitol, sorbitol, mannitol, gelatin, polymers (e.g., polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), crosslinked polyvinylpyrrolidone (crospovidone), carboxymethyl cellulose, polyethylene- polyoxypropylene-block polymers, and crosslinked sodium carboxymethyl cellulose (croscarmellose sodium)), titanium oxide, azo dyes, silica gel, fumed silica, talc, magnesium carbonate, vegetable stearin, magnesium stearate, aluminum stearate, stearic acid, antioxidants (e.g., vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium), citric acid, sodium citrate, parabens (e.g., methyl paraben and propyl paraben), petrolatum, dimethyl sulfoxide, mineral oil, serum proteins (e.g., human serum albumin), glycine, sorbic acid, potassium sorbate, water, salts or electrolytes (e.g., saline, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyacrylates, waxes, wool fat, lecithin, and com oil.

[0094] In some cases, a composition containing one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)) can be designed for oral or parenteral (including, without limitation, a subcutaneous, intramuscular, intravenous, intradermal, intra-cerebral, intrathecal, or intraperitoneal (i.p.) injection) administration to a mammal. Compositions suitable for oral administration include, without limitation, liquids, tablets, capsules, pills, powders, gels, and granules. In some cases, compositions suitable for oral administration can be in the form of a food supplement. In some cases, compositions suitable for oral administration can be in the form of a drink supplement. Compositions suitable for parenteral administration include, without limitation, aqueous and non-aqueous sterile injection solutions that can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient.

[0095] This document also provides methods for making one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)). Any appropriate method can be used to make one or more compounds provided herein. In some cases, a compound having the structure of Formula (I) can be made as described in Example 1.

[0096] This document also provides methods for using one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)). For example, one or more compounds having the structure of Formula (I) can be administered to a mammal (e.g., a human) having cancer (e.g., a brain cancer such as a glioma) to treat the mammal. In some cases, a mammal (e.g., a human) having cancer can be administered or instructed to self-administer one or more compounds having the structure of Formula (I).

[0097] Any appropriate mammal having cancer (e.g., a brain cancer such as a glioma) can be treated as described herein (e.g., by administering one or more compounds having the structure of Formula (I)). Examples of mammals that can have cancer and can be treated as described herein include, without limitation, humans, non-human primates (e.g., monkeys), horses, bovine species, porcine species, dogs, cats, mice, and rats. In some cases, a human having cancer (e g., a brain cancer such as a glioma) can be treated by administering one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)). For example, one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)) can be used to treat cancer (e.g., a brain cancer such as a glioma) in an adult human (e.g., a human that is 21 years of age or older). For example, one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)) can be used to treat cancer (e.g., a brain cancer such as a glioma) in a pediatric human (e.g., a human that is less than 21 years of age). For example, one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)) can be used to treat cancer (e.g., a brain cancer such as a glioma) in a human that is from about 1 day old to about 21 years old.

[0098] A mammal (e.g., a human) having any type of cancer can be treated as described herein (e.g., by administering one or more compounds having the structure of Formula (I)). In some cases, a cancer that can be treated as described herein can include one or more solid tumors. In some cases, cancer that can be treated as described herein can be a brain cancer. For example, a brain cancer that can includes one or more cancer cells having a genome including K27M substitution in a histone H3 polypeptide (e.g., a H3K27M mutation) can be treated as described herein. For example, a brain cancer that can includes one or more cancer cells having aberrant regulation of a STAT3 polypeptide can be treated as described herein. Examples of cancers that can be treated as described herein include, without limitation, gliomas (e.g., DIPGs such as pediatric DIPGs), glioblastomas, ovarian cancers, lymphomas, prostate cancers, lung cancers, leukemias, melanomas, liver cancers, and multiple myelomas. In some cases, the methods described herein also can include identifying a mammal as having cancer (e.g., a brain cancer such as a glioma). Examples of methods for identifying a mammal as having cancer include, without limitation, physical examination, laboratory tests (e.g., blood and / or urine), biopsy, imaging tests (e.g., X-ray, PET / CT, MRI, ultrasound and / or colonoscopies), nuclear medicine scans (e.g., bone scans), endoscopy, genetic tests, and / or Pap tests. Once identified as having cancer, a mammal can be treated as described herein (e.g., by administering one or more compounds having the structure of Formula (I)).

[0099] In some cases, one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)) can be administered to a mammal (e.g., a human) in need thereof (e.g., a human having cancer such as a brain cancer (e.g., a glioma)) to reduce the size of the cancer in the mammal. For example, one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)) can be administered to a mammal (e.g., a human) in need thereof (e.g., a human having cancer such as a brain cancer (e.g., a glioma)) as described herein to reduce the size of the cancer in the mammal. In some cases, the methods and materials provided herein can be used as described herein to reduce the number of cancer cells in the mammal by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent. In some cases, the methods and materials provided herein can be used as described herein to reduce the volume of one or more tumors in the mammal by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent.

[0100] In some cases, one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)) can be administered to a mammal (e.g., a human) in need thereof (e.g., a human having cancer such as a brain cancer (e.g., a glioma)) to improve survival of the mammal. For example, one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)) can be administered to a mammal (e.g., a human) in need thereof (e.g., a human having cancer such as a brain cancer (e.g., a glioma)) as described herein to improve survival of the mammal. In some cases, the methods and materials provided herein can be used as described herein to improve the survival of the mammal by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent. In some cases, the methods and materials provided herein can be used as described herein to improve the survival of the mammal by, for example, at least 6 months (e.g., about 6 months, about 8 months, about 10 months, about 1 year, about 1.5 years, about 2 years, about 2.5 years, about 3 years, about 4 years, about 5 years, or more).

[0101] One or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)) can be administered to a mammal (e.g., a human) by any appropriate route (e.g., oral, intranasal, inhalation, transdermal, and parenteral). One or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)) can be administered to a mammal locally or systemically. For example, one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)) can be administered locally by intraperitoneal (IP) injection, convection enhanced delivery (CED) infusion, or intravenous (IV) delivery to a mammal (e.g., a human). For example, one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)) can be administered systemically by oral administration to a mammal (e.g., a human).

[0102] One or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)) can be administered to a mammal (e.g., a human) having cancer (e.g., a brain cancer such as a glioma) in any appropriate amount (e.g., any appropriate dose). An effective amount of one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)) can be any amount that can treat a mammal having cancer without producing significant toxicity to the mammal. In cases where one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)) includes Br-Leu-Blue-COOH (Hi-Rf), an effective amount of Br-Leu-Blue- COOH (Hi-Rf) can be from about 1 milligrams per kilogram body weight (mg / kg) per day to about 300 mg / kg per day (e.g., from about 1 mg / kg per day to about 250 mg / kg per day, from about 1 mg / kg per day to about 200 mg / kg per day, from about 1 mg / kg per day to about 150 mg / kg per day, from about 1 mg / kg per day to about 100 mg / kg per day, from about 1 mg / kg per day to about 75 mg / kg per day, from about 1 mg / kg per day to about 50 mg / kg per day, from about 1 mg / kg per day to about 25 mg / kg per day, from about 25 mg / kg per day to about 300 mg / kg per day, from about 50 mg / kg per day to about 300 mg / kg per day, from about 75 mg / kg per day to about 300 mg / kg per day, from about 100 mg / kg per day to about 300 mg / kg per day, from about 150 mg / kg per day to about 300 mg / kg per day, from about 175 mg / kg per day to about 300 mg / kg per day, from about 200 mg / kg per day to about 300 mg / kg per day, from about 250 mg / kg per day to about 300 mg / kg per day, from about 25 mg / kg per day to about 250 mg / kg per day, from about 50 mg / kg per day to about 200 mg / kg per day, from about 75 mg / kg per day to about 175 mg / kg per day, from about 100 mg / kg per day to about 150 mg / kg per day, from about 25 mg / kg per day to about 75 mg / kg per day, from about 50 mg / kg per day to about 100 mg / kg per day, from about 75 mg / kg per day to about 125 mg / kg per day, from about 100 mg / kg per day to about 150 mg / kg per day, from about 125 mg / kg per day to about 175 mg / kg per day, from about 150 mg / kg per day to about 200 mg / kg per day, from about 175 mg / kg per day to about 225 mg / kg per day, from about 200 mg / kg per day to about 250 mg / kg per day, or from about 225 mg / kg per day to about 275 mg / kg per day). In cases where one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)) includes Br-Leu-Blue-NSFA (Hi-Rf), an effective amount of Br-Leu-Blue-NSFA (Hi-Rf) can be from about 1 mg / kg per day to 300 mg / kg per day (e.g., from about 1 mg / kg per day to about 250 mg / kg per day, from about 1 mg / kg per day to about 200 mg / kg per day, from about 1 mg / kg per day to about 150 mg / kg per day, from about 1 mg / kg per day to about 100 mg / kg per day, from about 1 mg / kg per day to about 75 mg / kg per day, from about 1 mg / kg per day to about 50 mg / kg per day, from about 1 mg / kg per day to about 25 mg / kg per day, from about 25 mg / kg per day to about 300 mg / kg per day, from about 50 mg / kg per day to about 300 mg / kg per day, from about 75 mg / kg per day to about 300 mg / kg per day, from about 100 mg / kg per day to about 300 mg / kg per day, from about 150 mg / kg per day to about 300 mg / kg per day, from about 175 mg / kg per day to about 300 mg / kg per day, from about 200 mg / kg per day to about 300 mg / kg per day, from about 250 mg / kg per day to about 300 mg / kg per day, from about 25 mg / kg per day to about 250 mg / kg per day, from about 50 mg / kg per day to about 200 mg / kg per day, from about 75 mg / kg per day to about 175 mg / kg per day, from about 100 mg / kg per day to about 150 mg / kg per day, from about 25 mg / kg per day to about 75 mg / kg per day, from about 50 mg / kg per day to about 100 mg / kg per day, from about 75 mg / kg per day to about 125 mg / kg per day, from about 100 mg / kg per day to about 150 mg / kg per day, from about 125 mg / kg per day to about 175 mg / kg per day, from about 150 mg / kg per day to about 200 mg / kg per day, from about 175 mg / kg per day to about 225 mg / kg per day, from about 200 mg / kg per day to about 250 mg / kg per day, or from about 225 mg / kg per day to about 275 mg / kg per day). In cases where one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)) includes Cl-Leu (Lo-Rf), an effective amount of Cl-Leu (Lo-Rf) can be from about 1 mg / kg per day to about 300 mg / kg per day (e.g., from about 1 mg / kg per day to about 250 mg / kg per day, from about 1 mg / kg per day to about 200 mg / kg per day, from about 1 mg / kg per day to about 150 mg / kg per day, from about 1 mg / kg per day to about 100 mg / kg per day, from about 1 mg / kg per day to about 75 mg / kg per day, from about 1 mg / kg per day to about 50 mg / kg per day, from about 1 mg / kg per day to about 25 mg / kg per day, from about 25 mg / kg per day to about 300 mg / kg per day, from about 50 mg / kg per day to about 300 mg / kg per day, from about 75 mg / kg per day to about 300 mg / kg per day, from about 100 mg / kg per day to about 300 mg / kg per day, from about 150 mg / kg per day to about 300 mg / kg per day, from about 175 mg / kg per day to about 300 mg / kg per day, from about 200 mg / kg per day to about 300 mg / kg per day, from about 250 mg / kg per day to about 300 mg / kg per day, from about 25 mg / kg per day to about 250 mg / kg per day, from about 50 mg / kg per day to about 200 mg / kg per day, from about 75 mg / kg per day to about 175 mg / kg per day, from about 100 mg / kg per day to about 150 mg / kg per day, from about 25 mg / kg per day to about 75 mg / kg per day, from about 50 mg / kg per day to about 100 mg / kg per day, from about 75 mg / kg per day to about 125 mg / kg per day, from about 100 mg / kg per day to about 150 mg / kg per day, from about 125 mg / kg per day to about 175 mg / kg per day, from about 150 mg / kg per day to about 200 mg / kg per day, from about 175 mg / kg per day to about 225 mg / kg per day, from about 200 mg / kg per day to about 250 mg / kg per day, or from about 225 mg / kg per day to about 275 mg / kg per day).

[0103] The effective amount of one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)) can remain constant or can be adjusted as a sliding scale or variable dose depending on the mammal’s response to treatment. Various factors can influence the actual effective amount used for a particular application. For example, the frequency of administration, duration of treatment, use of multiple treatment agents, route of administration, and / or severity of the cancer (e.g., brain cancer such as a glioma) in the mammal being treated may require an increase or decrease in the actual effective amount administered.

[0104] One or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)) can be administered to a mammal (e.g., a human) having cancer (e.g., a brain cancer such as a glioma) at any appropriate frequency. The frequency of administration can be any frequency that can treat a mammal having cancer without producing significant toxicity to the mammal. For example, the frequency of oral administration can be once a day or twice a day. For example, the frequency of CED infusion can be a 48-hour continuous infusion about once a week. The frequency of administration can remain constant or can be variable during the duration of treatment. As with the effective amount, various factors can influence the actual frequency of administration used for a particular application. For example, the effective amount, duration of treatment, use of multiple treatment agents, and / or route of administration may require an increase or decrease in administration frequency. In some cases, a frequency of administration can be as described elsewhere (see, e.g., Spinazzi et al., Lancet Oncol., 23(ll):1409-1418 (2022)).

[0105] One or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)) can be administered to a mammal (e.g., a human) having cancer (e.g., a brain cancer such as a glioma) for any appropriate duration. An effective duration for administering or using one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)) can be any duration that can treat a mammal having cancer without producing significant toxicity to the mammal. For example, the effective duration of CED infusion can be a 48-hour continuous infusion about once a week with 5-7 days of washout and can be repeated (e.g., repeated for treatment cycles). Multiple factors can influence the actual effective duration used for a particular treatment. For example, an effective duration can vary with the frequency of administration, effective amount, use of multiple treatment agents, and / or route of administration. In some cases, a duration of administration can be as described elsewhere (see, e g., Spinazzi et al., lancet Oncol., 23(11): 1409-1418 (2022)).

[0106] In some cases, methods for treating a mammal (e.g., a human) as described herein (e.g., by administering one or more compounds having the structure of Formula (I)) can include administering to the mammal the one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)) as the sole active ingredients. For example, a composition containing one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)) can include the one or more compounds as the sole active ingredients in the composition for treating a mammal (e.g., a human) having cancer (e.g., a brain cancer such as a glioma).

[0107] In some cases, methods for treating a mammal (e.g., a human) as described herein (e g., by administering one or more compounds having the structure of Formula (I)) also can include administering to the mammal one or more (e.g., one, two, three, or more) additional agents used to treat cancer and / or performing one or more (e.g., one, two, three, or more) therapies used to treat cancer. For example, a combination therapy used to treat a mammal (e.g., a human) having cancer (e.g., a brain cancer such as a glioma) can include administering to the mammal one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)), and administering to the mammal one or more (e.g., one, two, three, or more) additional agents used to treat cancer. In some cases, an additional agent that can be administered to a mammal to treat cancer can be a chemotherapeutic agent. In some cases, an agent that can be administered to a mammal to treat cancer can be an immune checkpoint inhibitor (e.g., a PD1 inhibitor, a PD-L1 inhibitor, a CTLA4 inhibitor, or combinations thereof). In some cases, an additional agent that can be administered to a mammal to treat cancer can be a cytotoxic agent. In cases where one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)) are used in combination with additional agents used to treat a mammal (e.g., a human) having cancer (e.g., a brain cancer such as a glioma), the one or more additional agents can be administered at the same time (e.g., in a single composition containing one or more compounds having the structure of Formula (I), and containing the one or more additional agents) or independently. For example, a composition including one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)) can be administered first, and the one or more additional agents administered second, or vice versa. In some cases, a combination therapy used to treat a mammal (e.g., a human) having cancer (e.g., a brain cancer such as a glioma) can include administering to the mammal one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)), and can include performing one or more (e.g., one, two, three, or more) therapies used to treat cancer. Examples of additional therapies that can be used to treat a mammal (e.g., a human) having cancer include, without limitation, radiation therapies, adoptive cell transfer therapies, and / or surgeries (e.g., surgeries to remove at least a portion of one or more tumors). In cases where one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)) are used in combination with one or more therapies used to treat a mammal (e.g., a human) having cancer, the one or more additional therapies can be performed at the same time or independently of the administration of the one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)). For example, one or more compounds provided herein (e.g., one or more compounds having the structure of Formula (I)) can be administered before, during, or after the one or more additional therapies are performed.

[0108] In some cases, the size of the cancer (e.g., the number of cancer cells and / or the volume of one or more tumors) present within a mammal can be monitored. Any appropriate method can be used to determine whether or not the size of die cancer present within a mammal is reduced. For example, imaging techniques can be used to assess the size of the cancer present within a mammal (e.g., a human).

[0109] The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims.

[0110] EXAMPLES

[0111] Example 1: Synthesis of exemplary compounds having the structure of Formula (I).

[0112] Compounds having the structure of Formula (I) induding Lo-Rf structures of Formula (I) and Hi-Rf structures of Formula (I)were synthesized as depicted in the synthetic schemes below. General Method for Synthesis of Compounds 1-6:

[0113] An oven dried round bottom with stir bar was charged with tBuOK (1.1 eq), purged with N2 and placed in an ice bath. THF was added to the round bottom and stirring was set to 500rpm. The tBuOK was allowed to dissolve for approximately 10 min. The desired acetophenone (1 eq) was then slowly added. The reaction mixture was allowed to stir on ice for 30 min after which the desired methyl ester (1.1 eq) was added slowly and the round bottom was removed from the ice bath and allowed to come to room temperature and react overnight. For workup the THF was removed under reduced pressure and the residue dissolved in water, acidified with IM HC1 and then transferred to a separatory funnel. The desired product was extracted with EtOAc (3x). The pooled organic layers were washed with brine (saturated NaCl) (2x), dried over MgSO4, filtered, and the solvent removed under reduced pressure to yield the desired crude product. The crude product was then purified by column chromatography utilizing the following solvent systems for each of the desired products:

[0114] Compound 1: Carried forward without purification.

[0115] Compound 2: 95:5 Hex:EtOAc (Yield: 50.08%) Compound 3: 96:4 Hex:EtOAc (Yield: 41.39%) Compound 4: 95:5 Hex:EtOAc (Yield: 41.99%) Compound 5: 80:20 Hex:EtOAc (Yield: 31.39%)

[0116] Compound 6: 80:20 Hex:EtOAc (Yield: 72.14%) (Hex = a mixture of hexanes; EtOAc = ethyl acetate) General Method for Synthesis of Compounds la / b, 2a / b, 5a / b-9a / b, 14a / b, 18a / b-22a / b: An oven dried round bottom with stir bar was charged with one of the desired 1,3- dione products (1 eq; Compounds 1-6) followed by EtOH and the desired Hydrazinobenzene HC1 salt (1.1 eq). The round bottom was then capped with a water jacket condenser and placed in an oil bath set to 95°C with stirring at 500 rpm. The reaction was allowed to proceed overnight. For workup of the reaction mixture the solvent was removed under reduced pressure to yield the crude desired products which were then purified by reverse phase HPLC.

[0117] Method for the synthesis of compounds 3a / b:

[0118] An oven dried vial already containing stir bar was charged with crude la / b (~1 eq) followed by DMF-DMA (8 eq). The vial was purged with Nz and stirring was set to 500 rpm. The reaction was allowed to proceed for 3hr at which point die reaction was quenched with water and the mixture was allowed to stir for an additional hour. For workup the quenched reaction mixture was transferred to a separatory funnel and the vial was washed repeatedly with EtOAc with washings being added to the separatory funnel. The organic layer was collected and then washed with water (4x). The organic layer was then washed with Brine (saturated NaCl) (2x) and subsequently collected, dried over MgSOn, filtered and the solvent removed under reduced pressure to yield crude 3a / b which were then subsequently purified by reverse phase HPLC.

[0119] Method for the synthesis of Compounds 4a / b, 16a / b & 17a / b:

[0120] An oven dried round bottom equipped with stir bar was charged with a desired crude pyrazole methyl ester (~1 eq; 18a / b, 21a / b or 22a / b) followed by MeOH, THE and aqueous IM NaOH (3 eq). Stirring was set to 500 rpm and the reaction was allowed to proceed for 2hr with reaction monitoring by thin layer chromatography run in a 92:8 HexiEtOAc solvent system. Upon complete disappearance of starting material, the reaction was halted and for workup was acidified by addition of IM HC1. From the acidified reaction mixture the desired products were extracted with EtOAc (4x) with pooling of organic fractions. The organic fraction was washed with Brine (saturated NaCl) (2x), dried over MgSC>4, filtered and the solvent removed under reduced pressure to yield the desired crude products which were then purified by reverse phase HPLC. Method for the synthesis of compounds lOa / b and 15a / b:

[0121] An oven dried round bottom equipped with stir bar was charged with a desired crude pyrazole methoxy derivative (~1 eq; 19a / b or 20a / b) followed by DCM. The round bottom was capped with a septum, purged with N2 and placed in an ice bath with stirring at 250 rpm. The reaction mixture was allowed to cool for lOmin after which BBn (5 eq) was added slowly and after 15 min post BBn addition the reaction mixture was allowed to come to room temperature and proceed overnight. For workup the round bottom was placed in an ice bath and allowed to cool for 10 min after which the reaction was quenched with sat. NaHCOs. After 10 min the reaction was allowed to come to room temperature and the desired products were extracted from the reaction mixture using EtOAc (3x) with pooling of the organic layers. The organic layer was then washed with brine (saturated NaCl) (2x), dried over MgSO4, filtered, and solvent removed under reduced pressure to yield the desired crude products which were then purified by reverse phase HPLC.

[0122] Method for the synthesis of compounds lla / b:

[0123] An oven dried round bottom equipped with stir bar was charged with crude la / b (~1 eq) followed by EtOH and water. The mixture was solubilized by sonicating for approx. 2 min. The round bottom was then charged with the following sequentially: NaNa (2 eq), Cui (0.1 eq), N,N'-Dimethylethylenediamine (0.18 eq) , and Sodium ascorbate (0.06 eq). After final addition the round bottom was topped with water-jacket condenser and purged with Na. The round bottom was placed in a preheated oil bath set to auto-temp 100°C and stirred at 400 rpm. The reaction was allowed to proceed overnight. To halt the reaction the round bottom was removed from the oil bath and allowed to come to room temperature at which point water was added along with IM EDTA pH=8 and EtOAc to quench the reaction. This mixture was allowed to stir for 2hr at which point the desired products were extracted from the reaction mixture with EtOAc (4x) with organic layers being pooled and then washed sequentially with Sat. NaHCOs (2x), Brine (saturated NaCl) (2x) and the organic layer was collected, dried over MgSO4, filtered, and the solvent removed under reduced pressure to yield crude 1 la / b which were then purified by reverse phase HPLC. Method for the synthesis of compounds 12a / b:

[0124] Ann oven dried round bottom equipped with stir bar was charged with crude la / b (~1 eq) followed by BjPim, 2-KEH, and Xphos. The round bottom was then capped with septa and purged with N2 after which IP AC was added, and the round bottom was placed in an oil bath with auto-temp set to 55°C and stirring set to 500rpm. After 20min Palladium (II) acetate was added to the reaction by dissolving in IP AC (under N2) the reaction was allowed to proceed overnight. Reaction progress was monitored by thin layer chromatography using a 98:2 DCM:EtOH solvent system which confirmed complete consumption of starting material. For workup the reaction mixture was transferred to a separatory funnel and the desired products were extracted using EtOAc (2x) and the organic layers pooled. The pooled organic layer was then washed with NaHCCh 5% aq (4x), Brine (saturated NaCl) (2x) and the organic layer was collected dried over MgSCh, filtered and then the solvent was removed under reduced pressure to yield crude 12a / b which were then purified by reverse phase HPLC. Method for the synthesis of compounds 13a / b:

[0125] To oven an oven dried vial equipped with stir bar HPLC purified 12a (1 eq) or 12b (1 eq) was added followed by methyl boronic acid (MeB(OH)2; 10 eq) and DCM containing 5% (v / v) TFA. The vial was capped and stirred at 300rpm with reaction progress being monitored via thin layer chromatography using a 98:2 DCM:EtOH solvent system. After being allowed to react for 5hr and no further conversion being noted the solvent was removed under reduced pressure. Following solvent removal, the product was redissolved in MeOH followed by addition of 0.1M HC1. The solvent was then removed again with this process being repeated 2x to yield 13a or 13b as pure products.

[0126] Example 2: Exemplary compounds having the structure of Formula (I).

[0127] Exemplary compounds having the structure of Formula (I) are shown in Table 1, with groups R1, R2, and R3corresponding to groups numbered in the structure shown below.

[0128]

[0129] Table 1 shows the STAT3 inhibition, cancer selectivity, and blood-brain barrier (BBB) penetrability of exemplary compounds having the structure of Formula (I) and having the shown side chain modifications. Each analog is represented by a compound number, and the regioisomer of each compounds structure is represented by ‘a’ (Lo-Rf) & ‘b’ (Hi-Rf).

[0130] The percentage of STAT3 inhibition at 10 μM was calculated based on a 24-hour STAT3-luciferase reporter assay conducted in HEK293T cells.

[0131] Cancer selectivity index was calculated based on the ICso in normal human astrocytes (NHA) against DIPG cell line (DIPG XVIII). The higher number represents selection of killing tumor cells before normal cells.

[0132] The BBB score is an algorithm that was used to determine the ability of drug molecule to penetrate BBB based on 5 physicochemical descriptors. The higher number represents more BBB penetrability.

[0133]

[0134]

[0135]

[0136]

[0137] Example 3: Characterization of exemplary compounds having the structure of Formula (I)

[0138] Additional characteristics of exemplary structures of Formula (I) were evaluated. The structures of compound la (also referred to as Br-Leu and Lo-Rf) is shown in Figure 1 A. The structures of compound lb (also referred to as Br-Leu-Blue and Hi-Rf) is shown in Figure IB. Additional information related to compounds la and lb are as set forth in Table 2.

[0139] Table 2. The percentage of STAT3 inhibition at 10 μM was calculated based on the STAT3 - luciferase assay conducted in HEK293 cells. Cancer selectivity index was calculated based on the ICso in normal human astrocytes (NHA) against DIPG cell line (DIPG XVHI), and the higher number represented selection of killing tumor cells before normal cells. The BBB score is an algorithm that was used to determine the ability of drug molecule to penetrate BBB based on 5 physicochemical descriptors, and the higher number represented more BBB penetrability.

[0140] Exemplary structures of Formula (I) were assessed for their ability to inhibit IL6- induced STAT3 activation. GBM (dBTl 14) cells were pre-treated with drug compounds for 1 hour, and then STAT3 was acutely activated with IL6 for 15 minutes. The cells were subsequently harvested and subjected to analyze the level of phosphorylated STAT3 using immunoblot. Immunoblot analysis STAT3 inhibition is shown in Figures 2A-2E. Based on the level of phospho-STAT3 inhibition.

[0141] Cell viability in the presence of exemplary structures of Formula (I) was evaluated in both normal cells and in tumor cell lines. Normal cell lines evaluated included normal human astrocytes (NHA). Cancer cell lines evaluated included DIPG cell lines DIPG XVII, DID 22, DIPG IV, and PED 17. Cells were seeded at 5,000 cells per well in 96-well plates and allow to recover overnight. The next day, the cells were treated with different concentration of drugs a maximal of 0.5% DMSO. DMSO were used as vehicle to dissolve the lead compounds. 0.5% DMSO were used as vehicle to treat controls. Cells were treated with 72 hours of lead compounds before the cell viabilities were measured using CellTiter Gio 2.0 (Promega) according to manufacturer’s recommendation. Cell viability is shown in Figures 3A-3E.

[0142] To assess the mechanism of action of exemplary structures of Formula (1) in inhibiting STAT3, STAT3 inhibition was also evaluated using a known STAT3 inhibitor (WP1066) and a JAK2 inhibitor (ruxolitinib). Tumor cells (dBTl 14) were challenged with prolonged IL6-induced STAT3 activation in the presence of either WP1066, ruxolitinib, or exemplary structures of Formula (I) for 24 hours. The cells were harvested at the end of 24 hours treatment and subjected to immunoblot analysis (Figure 4). As shown in Figure 4, the STAT3 phosphorylation status was not affected by prolong presence of WP 1066 or ruxolitinib, yet compounds lb and 4b maintained inhibition of STAT3 phosphorylation despite prolonged exposure to IL6, suggesting a inhibit STAT3 activation by a novel mechanism.

[0143] Binding affinity of exemplary structures of Formula (I) to STAT3 was evaluated. Binding affinity was measured using isothermal titration calorimetry (ITC). ITC is a label- free methods that measures binding of two molecules where the two molecules release or absorb heat upon binding. The integrated heat peaks are presented in a Wiseman plot against the molar ratio of the drug, and the binding signature (e.g., free energy, binding enthalpy and entropy factor) are plotted for compound lb (Figure 5 A) and compound 4b (FigureSB).

[0144] The mechanism of action of exemplary structures of Formula (I) was further evaluated using cells in which STAT3 expression was knocked-out. A Pearson correlation of compounds la, lb, 3b, 4b, and 8a of percent STAT3 inhibition was plotted against ICso tested DIPG XVII (Figure 6A). Knocking out STAT3 led to loss of potency of compound 4b with a right shift of cell viability (Figure 6B). Knocking out STAT3 resulted in increased IC50values in cells treated with compound 4b (Figure 6C). Immunoblotting was used to confirm CRISPR knockout of STAT3 (Figure 6D).

[0145] The ability of exemplary structures of Formula (I) to inhibit STAT3 in vivo was also evaluated. Mice were implanted orthotopically with DIPG XVII in the pons and then subsequently treated with compound 4b (150 μM) through continuous direct infusion for 7 days using an osmotic (ALZET) mini pump. Once the drug infusion was completed, the pump was removed, and the animals were monitored for survival (Figure 7).

[0146] The solubility of exemplary structures of Formula (I) was evaluated. Compound 4b was over 15-fold more soluble than compound la and about 85-fold more soluble than compound lb (Figure 8).

[0147] The stability of exemplary structures of Formula (I) was also evaluated by subjecting the compounds to 37°C with shaking at 800 rpm. Compound 4b demonstrated higher stability as compared to WP1066 (Figure 9).

[0148] STAT3 inhibitors such as WP1066 and Stattic have a Michael acceptor which covalently bind to STAT3 resulting in degradation of STAT3. Overnight induction with IL6 followed by treatment with WP1066, Stattic, or exemplary structures of Formula (I) showed that WP1066 and Stattic provided biological feedback to further potentiate STAT3 activation rather than inhibition while none of the exemplary structures of Formula (I) exhibited this effect (Figure 10).

[0149] STAT3 activity in correlation to cell viability was also evaluated. STAT3 activity is shown in Figure 11.

[0150] Next, the potency of exemplary structures of Formula (I) was evaluated. CRISPR was used to knockout STAT3 in the DIPG cell line SF8628, and the knockout cells and cells were treated with WP1066. Knocking out STAT3 had no impact on potency of WP1066 after 48 hours (Figure 12A), suggesting that the mechanism of action of WP1066 is not dependent on the presence of STAT3 and thus is not the main target of WP 1066. Likewise, knocking out STAT3 did not impact potency of WP 1066 as measured by ICso values (Figure 12B).

[0151] Pharmacokinetics of exemplary structures of Formula (I) were evaluated. Mice were subjected to an acute convection-enhanced delivery (CED) infusion of 150 μM compound 4b. The percent of compound 4b that remained in the brain tissue 30 minutes after is shown in Figure 13 A. In another experiment, mice were given a single dose of oral gavage (40 mg / kg) of compound 4b, and tissues were harvested 1 hour after the oral gavage. A tissue distribution of compound 4b in the harvested tissues is shown in Figure 13B. A tissue to plasma ratio of the amount of compound 4b remaining in each mouse 1 hour post oral gavage is shown in Figure 13C.

[0152] Example 4: Compound 4b and the JAK-STAT pathway

[0153] A role for compound 4b in the JAK-STAT pathway was evaluated.

[0154] A Cellular Thermal Shift Assay (CETSA), a label-free technique was used to evaluate protein targets of compound 4b. Protein lysates from dBTl 14 (GBM cell line) were harvested, lysed and co-incubated with 50 μM of vehicle (DMSO), ruxolitinib, or 4b in an ex vivo experiment. The treated protein lysates were equally divided, and each aliquot was subjected to heat degradation ranging from 41°C - 60°C. The resulted lysates were analyzed using immunoblotting. In comparison to DMSO or ruxolitinib treated protein lysates, 4b showed protection against heat degradation of JAK1, JAK2, TYK2, STAT1, STAT3 and STATS but not AKT or ERK (Figure 14). Compound 4b inhibited phosphorylation of JAK1, JAK2, TYK2, STAT1, STAT3 and STATS during the IL6-induced pathway activation (Figure 15).

[0155] Compound 4b provided prolonged inhibition of STAT pathway during IL6- or IFN-y- induced activation. Following 24-hour serum starvation dBTl 14 (GBM cells) were pretreated with the indicated concentrations of 4b, WP1066, or ruxolitinib for 1 hour followed by acute induction with either IL16 or IFN-y for 15 minutes. The cells were subsequently harvested and subjected immunoblotting to analyze the level of phosphorylated on the targets indicated in Figures 16A and 16B. Overnight induction with IL6 in dBTl 14 cells (in 10% FBS containing media) concurrently with the indicated concentrations of 4b, WP1066, or ruxolitinib along with either IL6 or IFN-y for 24 hours. The cells were subsequently harvested and subjected immunoblotting to analyze the level of protein expression on the targets indicated in Figures 16C and 16D which showed that Compound 4b maintains continuous pathway inhibition while both ruxolitinib and WP1066 showed biological feedback to potentiate STAT3 activation rather than inhibition.

[0156] Together, these results demonstrate that compound 4b can be used as a pan inhibitor for the JAK-STAT pathway.

[0157] Example 5: Treating Cancer

[0158] A human (e.g., a human that is less than 21 years of age) identified as having DIPG (e.g., pediatric DIPG) is administered a composition including one or more compounds having the structure of Formula (I). The administered combination can reduce the number of cancer cells present within the human.

[0159] Example 6: Treating Cancer

[0160] A human (e.g., a human that is less than 21 years of age) identified as having DIPG (e.g., pediatric DIPG) is administered a composition including one or more compounds having the structure of Formula (I). The administered combination can reduce the volume of one or more tumors present within the human. OTHER EMBODIMENTS

[0161] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A compound having a structure of Formula (I):wherein R1is S(O)aN=C(Rlb)N(Rla)2 or C(O)ORlc; wherein each Rlais independently H or C1-C6alkyl, Rlbis H or C1-C6alkyl, and Rlcis H or C1-C6alkyl; wherein R2is C6-C10aryl optionally substituted with halogen, C1-C6alkoxy, or C1-C6alkyl; wherein R3is C6-C10aryl optionally substituted with halogen, C1-C6alkoxy, or C1-C6alkyl; and wherein one of R2or R3is C1-C6alkyl and one of R2or R3is C6-C10aryl optionally substituted with halogen, C1-C6alkoxy, or C1-C6alkyl.

2. The compound of claim 1, wherein said compound has the structure:

3. The compound of claim 1, wherein said compound has the structure:

4. A compound having a structure of Formula (I):wherein R1is S(O)2N(Rla)2; wherein each Rlais independently H or C1-C6alkyl; wherein R2is C6-C10aryl substituted with Cl, C1-C6alkoxy, or C1-C6alkyl; wherein R3is Cs-Cio aryl substituted with Cl, C1-C6alkoxy, or C1-C6alkyl; and wherein one of R2or R3is C1-C6alkyl and one of R2or R3is C6-C10aryl substituted with Cl, C1-C6alkoxy, or C1-C6alkyl.

5. The compound of claim 4, wherein said compound has the structure:

6. A pharmaceutical composition comprising the compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

7. A method for treating a mammal having a cancer, wherein said method comprises administering the compound of any one of claims 1-5 or the pharmaceutical composition of claim 6 to said mammal.

8. The method of claim 7, wherein said mammal is a human.

9. The method of claim 8, wherein said human is less than 21 years of age.

10. The method of any one of claims 7-9, wherein said cancer is a glioma.

11. The method of claim 10, wherein said glioma is a diffuse intrinsic pontine glioma.

12. The method of any one of claims 10-11, wherein said cancer includes one or more cancer cells having a genome including K27M substitution in a histone H3 polypeptide.

13. The method of any one of claims 7-12, wherein the mammal is identified as having said cancer.

14. The method of any one of claims 7-13, said method further comprising subjecting said mammal to radiation therapy.

15. A method for inhibiting a signal transducer and activator of transcription 3 (STAT3) polypeptide in a mammal, wherein said method comprises administering the compound of any one of claims 1-5 or the pharmaceutical composition of claim 6 to said mammal.

16. The method of claim 15, wherein said mammal is a human.

17. The method of claim 16, wherein said human is less than 21 years of age.

18. The method of any one of claims 15-17, wherein said mammal has a cancer.

19. The method of claim 18, wherein said cancer is a glioma.

20. The method of claim 19, wherein said glioma is a diffuse intrinsic pontine glioma.

21. The method of any one of claims 19-20, wherein said cancer includes one or more cancer cells having a genome induding K27M substitution in a histone H3 polypeptide.

22. The use of a compound of any one of claims 1-5 to treat a mammal having a cancer.

23. The compound of any one of claims 1-5 for use in the preparation of a medicament to treat a cancer.

24. The compound of any one of claims 1-5 for use in the treatment of a cancer.

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