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US-12616678-B2 - Methods to of aldehyde dehydrogenases for treatment of cancer

US12616678B2US 12616678 B2US12616678 B2US 12616678B2US-12616678-B2

Abstract

Disclosed are compositions and methods for inhibiting aldehyde dehydrogenases. In further aspects, treatment of cancers by inhibiting aldehyde dehydrogenases with the disclosed compositions are also disclosed.

Inventors

  • Gavin P. Robertson
  • Venkata Saketh Sriram DINAVAHI
  • Raghavendra Gowda Chandagalu DORESWAMY
  • Todd Schell
  • Kishore PUNNATH

Assignees

  • THE PENN STATE RESEARCH FOUNDATION

Dates

Publication Date
20260505
Application Date
20210610

Claims (20)

  1. 1 . A method of treating cancer in a subject, comprising: administering a therapeutically effective amount of a checkpoint inhibitor or a BRAF inhibitor and a composition comprising a compound of Formula I wherein, X is S or Se; L is a C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 5 -C 6 cycloalkyl, C 5 -C 6 heterocycloalkyl, or phenyl, any of which is optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, NH 2 , CO 2 H, CO 2 C 1 -C 6 alkyl, halide, OH, or NO 2 ; n is 0, 1, 2, or 3; R 1 and R 2 are each independently chosen from H, F, Cl, Br, I, NO 2 , OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, or C 1 -C 6 haloalkyl, or a pharmaceutically acceptable salt thereof.
  2. 2 . The method of claim 1 , wherein L is a C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, or C 5 -C 6 cycloalkyl, any of which are optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, NH 2 , CO 2 H, CO 2 C 1 -C 6 alkyl, halide, OH, or NO 2 .
  3. 3 . The method of claim 1 , wherein L is a C 5 -C 6 heterocycloalkyl optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, NH 2 , CO 2 H, CO 2 C 1 -C 6 alkyl, halide, OH, or NO 2 .
  4. 4 . The method of claim 1 , wherein L is a phenyl optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, NH 2 , CO 2 H, CO 2 C 1 -C 6 alkyl, halide, OH, or NO 2 .
  5. 5 . The method of claim 1 , wherein L is a heteroaryl optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, NH 2 , CO 2 H, CO 2 C 1 -C 6 alkyl, halide, OH, or NO 2 .
  6. 6 . The method of claim 1 , wherein at least one of R 1 and R 2 is a halogen.
  7. 7 . The method of claim 1 , wherein at least one of R 1 and R 2 is H.
  8. 8 . The method of claim 1 , wherein the compound is KS100 free base (FB): 2-[4-(5, 7-Dibromo-2, 3-dioxo-2, 3-dihydroindol-1-ylmethyl)benzyl]isothiourea.
  9. 9 . The method of claim 1 , wherein compound is selected from the group consisting of: KS104 (3a): 2-[4-(2,3-Dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isothiourea hydrobromide; KS104FB: 2-[4-(2,3-Dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isothiourea; KS108 (3b):2-[4-(5-Bromo-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isothiourea hydrobromide; KS100 FB: 2-[4-(5-Bromo-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isothiourea; KS110 (3c): 2-[4-(7-Bromo-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isothiourea hydrobromide; KS110 FB: 2-[4-(7-Bromo-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isothiourea; KS112 (3d): 2-[4-(5-Chloro-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isothiourea hydrobromide; KS112 FB: 2-[4-(5-Chloro-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isothiourea; KS114 (3e): 2-[4-(7-Chloro-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isothiourea hydrobromide; KS114 FB: 2-[4-(7-Chloro-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isothiourea; KS116 (3f): 2-[4-(5-Fluoro-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isothiourea hydrobromide; KS116 FB: 2-[4-(5-Fluoro-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isothiourea; KS118 (3g): 2-[4-(7-Fluoro-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isothiourea hydrobromide; KS118 FB: 2-[4-(7-Fluoro-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isothiourea; KS106 (3h): 2-[4-(2,3-Dioxo-5-trifluoromethyl-2,3-dihydroindol-1-ylmethyl)benzyl]isothiourea hydrobromide; KS106 FB: 2-[4-(2,3-Dioxo-5-trifluoromethyl-2,3-dihydroindol-1-ylmethyl)benzyl]isothiourea; KS122 (3i): 2-[4-(2,3-Dioxo-7-trifluoromethyl-2,3-dihydroindol-1-ylmethyl)benzyl]isothiourea hydrobromide; KS122 FB: 2-[4-(2,3-Dioxo-7-trifluoromethyl-2,3-dihydroindol-1-ylmethyl)benzyl]isothiourea; KS100 (3j): 2-[4-(5, 7-Dibromo-2, 3-dioxo-2, 3-dihydroindol-1-ylmethyl)benzyl]isothiourea hydrobromide; KS100 FB: 2-[4-(5, 7-Dibromo-2, 3-dioxo-2, 3-dihydroindol-1-ylmethyl)benzyl]isothiourea; KS102 (3k): 2-[4-(5,7-Dichloro-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isothiourea hydrobromide; KS102 FB: 2-[4-(5,7-Dichloro-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isothiourea; KS120 (3l): 2-[4-(7-Bromo-5-fluoro-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isothiourea hydrobromide; KS120 FB: 2-[4-(7-Bromo-5-fluoro-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isothiourea; KS105 (4a): 2-[4-(2,3-Dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isoselenourea hydrobromide; KS105 FB: 2-[4-(2,3-Dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isoselenourea; KS109 (4b): 2-[4-(5-Bromo-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isoselenourea hydrobromide; KS109 FB: 2-[4-(5-Bromo-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isoselenourea; KS111 (4c): 2-[4-(7-Bromo-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isoselenourea hydrobromide; KS111 FB: 2-[4-(7-Bromo-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isoselenourea; KS113 (4d): 2-[4-(5-Chloro-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isoselenourea hydrobromide; KS113 FB: 2-[4-(5-Chloro-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isoselenourea; KS115 (4e): 2-[4-(7-Chloro-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isoselenourea hydrobromide; KS115 FB: 2-[4-(7-Chloro-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isoselenourea; KS117 (4f): 2-[4-(5-Fluoro-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isoselenourea hydrobromide; KS117 FB: 2-[4-(5-Fluoro-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isoselenourea; KS119 (4g): 2-[4-(7-Fluoro-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isoselenourea hydrobromide; KS119 FB: 2-[4-(7-Fluoro-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isoselenourea; KS107 (4h): 2-[4-(2,3-Dioxo-5-trifluoromethyl-2,3-dihydroindol-1-ylmethyl)benzyl]isoselenourea hydrobromide; KS107 FB: 2-[4-(2,3-Dioxo-5-trifluoromethyl-2,3-dihydroindol-1-ylmethyl)benzyl]isoselenourea; KS123 (4i): 2-[4-(2,3-Dioxo-7-trifluoromethyl-2,3-dihydroindol-1-ylmethyl)benzyl]isoselenourea hydrobromide; KS123 FB: 2-[4-(2,3-Dioxo-7-trifluoromethyl-2,3-dihydroindol-1-ylmethyl)benzyl]isoselenourea; KS101 (4j): 2-[4-(5, 7-Dibromo-2, 3-dioxo-2, 3-dihydroindol-1-ylmethyl)benzyl]isoselenourea hydrobromide; KS101 FB: 2-[4-(5, 7-Dibromo-2, 3-dioxo-2, 3-dihydroindol-1-ylmethyl)benzyl]isoselenourea; KS103 (4k): 2-[4-(5, 7-Dichloro-2, 3-dioxo-2, 3-dihydroindol-1-ylmethyl)benzyl]isoselenourea hydrobromide; KS103 FB: 2-[4-(5, 7-Dichloro-2, 3-dioxo-2, 3-dihydroindol-1-ylmethyl)benzyl]isoselenourea; KS121 (4l): 2-[4-(7-Bromo-5-fluoro-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isoselenourea hydrobromide; and KS121 FB: 2-[4-(7-Bromo-5-fluoro-2,3-dioxo-2,3-dihydroindol-1-ylmethyl)benzyl]isoselenourea.
  10. 10 . The method of claim 1 , wherein the compound is KS100 ((3j): 2-[4-(5, 7-Dibromo-2, 3-dioxo-2, 3-dihydroindol-1-ylmethyl)benzyl]isothiourea hydrobromide).
  11. 11 . The method of claim 1 , wherein the composition further comprises a pharmaceutically acceptable carrier and wherein the pharmaceutically acceptable carrier comprises liposomes.
  12. 12 . The method of claim 1 , wherein the checkpoint inhibitor is a PD-1 inhibitor, PD-L1 inhibitor, or CTLA4 inhibitor.
  13. 13 . The method of claim 12 , wherein the checkpoint inhibitor is chosen from anti-PD-1, nivolumab, pembrolizumab, cemiplimab, ipilimumab, atezolizumab, avelumab, durvalumab, or combinations thereof.
  14. 14 . The method of claim 1 , wherein the BRAF inhibitor is sorafenib, vemurafenib, dabrafenib, encorafenib, or combinations thereof.
  15. 15 . The method of claim 1 , wherein the cancer is a cancer characterized by overexpression of one or more aldehyde dehydrogenases selected from ALDH1A1, ALDH1A2, ALDH1A3, ALDH1L1, ALDH2, ALDH3A1, ALDH5A1, ALDH18A1, or a combination of any two or more thereof.
  16. 16 . The method of claim 1 , wherein the cancer is selected from the group consisting of: melanoma, liver cancer, prostate cancer, breast cancer, brain cancer, stomach cancer, pancreas cancer, blood cell cancer, uterine cancer, cervical cancer, ovarian cancer, lung cancer, colon cancer, connective tissue cancer (sarcomas), soft tissue cancer, and head and neck squamous cell carcinoma.
  17. 17 . A composition comprising a checkpoint inhibitor or a BRAF inhibitor and a composition comprising a compound of Formula I wherein, X is S or Se; L is a C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 5 -C 6 cycloalkyl, C 5 -C 6 heterocycloalkyl, or phenyl, any of which is optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, NH 2 , CO 2 H, CO 2 C 1 -C 6 alkyl, halide, OH, or NO 2 ; n is 0, 1, 2, or 3; R 1 and R 2 are each independently chosen from H, F, Cl, Br, I, NO 2 , OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, or C 1 -C 6 haloalkyl, or a pharmaceutically acceptable salt thereof.
  18. 18 . The composition of claim 17 , wherein L is a C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, or C 5 -C 6 cycloalkyl, any of which are optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, NH 2 , CO 2 H, CO 2 C 1 -C 6 alkyl, halide, OH, or NO 2 .
  19. 19 . The composition of claim 17 , wherein L is a C 5 -C 6 heterocycloalkyl optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, NH 2 , CO 2 H, CO 2 C 1 -C 6 alkyl, halide, OH, or NO 2 .
  20. 20 . The composition of claim 17 , wherein L is a phenyl optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, NH 2 , CO 2 H, CO 2 C 1 -C 6 alkyl, halide, OH, or NO 2 .

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a national stage application filed under 35 U.S.C. § 371 of PCT/US2021/036793, filed Jun. 10, 2021, which claims the benefit of priority to U.S. Provisional Application 63/037,328, filed Jun. 10, 2020, the contents of which are incorporated by reference herein in their entirety. BACKGROUND A major mechanism by which cancer cells develop resistance is through upregulation of the aldehyde dehydrogenases (ALDHs). The 19 human ALDH isozymes are broadly defined as a superfamily of NAD(P)+-dependent enzymes and participate in aldehyde metabolism, catalyzing the oxidation of exogenous aldehydes (drugs and ethanol) and endogenous aldehydes (lipids, amino acids, or vitamins) into their corresponding carboxylic acids. The ALDHs confer a survival advantage to metabolically active cancer cells, by oxidizing aldehydes that accumulate and cause oxidative damage, into less toxic, more soluble carboxylic acids. Accordingly, ALDH overexpression is linked to poor overall and shorter recurrence-free survival in gastric, breast, lung, pancreatic and prostate carcinomas, head and neck squamous cell carcinomas (HNSCCs), and melanomas, among others. There is a continuing need for ALDH inhibitors to inhibit tumors and treat cancer in a subject in need thereof. The subject matters disclosed herein addresses these and other needs. SUMMARY In accordance with the purposes of the disclosed materials and methods, as embodied and broadly described herein, the disclosed subject matter, in one aspect, relates to compounds, compositions and methods of making and using compounds and compositions. In specific aspects, the disclosed subject matter relates to compositions and methods for inhibiting aldehyde dehydrogenases. In further aspects, the disclosed subject matter relates to the treatment of cancers by inhibiting aldehyde dehydrogenases. In a further aspect, the disclosed subject matter relates to combinations of aldehyde dehydrogenase inhibitors and checkpoint inhibitors, such as PD-1 and PD-L1. Additional advantages will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the aspects described below. The advantages described below will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive. BRIEF DESCRIPTION OF THE FIGURES The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects described below. FIGS. 1A-1F. illustrate that the ALDH family is collectively important in melanoma. Western blot showing ALDH1A1, 2 and 3A1 expression levels in normal human fibroblasts (FF2441), melanocytes (NHEM), radial growth phase (RGP), vertical growth phase (VGP) and metastatic melanoma cell lines. ALDH expression in general increased during disease progression and was not dependent on BRAF mutational status. Alpha-enolase served as the loading control (FIG. 1A). Data from the TCGA database showing slightly better survival with ALDH1A1 and 2 overexpression (FIG. 1B) and worse survival with ALDH3A1 overexpression (FIG. 1C) in melanoma patients. The data are available through the UCSC Xena Cancer Browser. Individual siRNA knockdown of ALDH1A1, 2 and 3A1 did not significantly reduce the growth of UACC 903 cells after 72 hours in an MTS assay. siRNA to BRAF and ALDH18A1 served as positive controls. Scrambled siRNA served as the negative control (FIG. 1D). siRNA knockdown of ALDH1A1, 2, 3A1, 18A1 and BRAF in UACC 903 cells was confirmed via western blot. Alpha-enolase served as loading control (FIG. 1E). Pharmacological inhibition of ALDH1A1, 2 and 3A1 using ALDH isoform-specific inhibitors (Cpd 3, CVT10216 and CB7, respectively) and the multi-ALDH isoform inhibitor, DEAB, revealed multi-ALDH isoform inhibition was most effective in inhibiting UACC 903 cell growth (FIG. 1F). FIG. 2. Synthesis of the ALDH1A1, 2 and 3A1 inhibitor, called KS100. KS100 was synthesized from 5,7-dibromoisatin followed by benzylation as detailed in the materials and methods. FIGS. 3A-3B. KS100 (FIG. 3A) and NanoKS100 (FIG. 3B) preferentially killed melanoma cells. Cell killing IC50s for KS100 and NanoKS100 against BRAF mutant (UACC 903, 1205 Lu) and wildtype (C8161.CI9, MelJuSo) melanoma cell lines were calculated and compared to that of normal human fibroblasts (FF2441) and melanocytes (NHEM). KS100 was ˜4.5-fold and NanoKS100 was ˜5-fold more selective for killing melanoma cells compared to FF2441 and NHEM cells. FIGS. 4A-4H. Development and characterization of the nanoliposomal formulation of KS100, called NanoKS100. NanoKS100 consists of an aqueous core surrounded by a phospholipid bilayer. KS100 is contained within the phospholipid bilayer (FIG. 4