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US-12616753-B2 - HSP70 inhibitors and methods of using same

US12616753B2US 12616753 B2US12616753 B2US 12616753B2US-12616753-B2

Abstract

The disclosure provides in one aspect compounds, and compositions comprising such compounds, that can be used to treat, ameliorate, and/or prevent cancer, especially colorectal cancer (CRC). In certain embodiments, the compounds of the disclosure inhibit HSP70. In other embodiments, the compounds of the disclosure promote or increase immune cell recruitment to a cancer. In yet other embodiments, the compounds of the disclosure promote and/or increase immune cell infiltration in a cancer.

Inventors

  • Maureen E. Murphy
  • Joseph Salvino
  • Donna L. George
  • Julia LEU

Assignees

  • THE WISTAR INSTITUTE
  • THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA

Dates

Publication Date
20260505
Application Date
20210330

Claims (20)

  1. 1 . A compound of formula (I), or a salt, solvate, enantiomer, or tautomer thereof: BINDER-X—(Z 1 ) m1 —Y—(Z 2 ) m2 -L (I), wherein: BINDER is selected from the group consisting of: wherein: R 2 and R 3 are each independently R 1 , or R 2 and R 3 combine to form —O—, —S—, —NH—, or —N(C 1 -C 6 alkyl)-; W 1 is C(R 1 ) or N; W 2 is C(R 1 ) or N; each occurrence of R 1 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, fluoro, chloro, bromo, iodo, cyano, nitro, —N(R′)(R′), —C(═O)OR′, and —C(═O)NR′R′, wherein each occurrence of R′ is independently H or C 1 -C 6 alkyl; n1 is selected from the group consisting of 0, 1, 2, 3, and 4; n2 is selected from the group consisting of 0, 1, 2, 3, 4, and 5; X is selected from the group consisting of —(CH 2 ) 1-5 , —(CH 2 CH 2 O) 1-5 , —(OCH 2 CH 2 ) 1-5 , —NHS(═O) 2 —*, —S(═O) 2 NH—*, —OC(═O)NH—*, and —NHC(═O)O—*, wherein the bond marked with * is formed with Z 1 ; Y is selected from the group consisting of a chemical bond, *—OC(═O)—, and *—C(═O)O—, wherein the bond marked with * is formed with Z 1 ; each occurrence of Z 1 is independently selected from the group consisting of bond, —CH 2 —, —OCH 2 CH 2 —, and —CH 2 CH 2 O—; each occurrence of Z 2 is independently selected from the group consisting of bond, —CH 2 —, —OCH 2 CH 2 —, and —CH 2 CH 2 O—; m1 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; m2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; with the proviso that X—(Z 1 ) m1 —Y—(Z 2 ) m2 -L does not comprise a O—O bond; L is a group selected from the group consisting of: wherein: each occurrence of R a , R b , R c , R d , R e , R f , R g , and R h is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, fluoro, chloro, bromo, iodo, cyano, nitro, —N(R″)(R″), —C(═O)OR″, and —C(═O)NR″R″, wherein each occurrence of R″ is independently H or C 1 -C 6 alkyl; R i and R j are independently H or optionally substituted C 1 -C 6 alkyl; each occurrence of n, r1, r2, r3, r6, and r7 is independently selected from the group consisting of 1, 2, 3, 4, and 5; each occurrence of r4 is selected from the group consisting of 1, 2, and 3; and each occurrence of r5 is selected from the group consisting of 1, 2, 3, and 4.
  2. 2 . The compound of claim 1 , wherein BINDER is selected from the group consisting of: wherein: n3 is selected from the group consisting of 0, 1, 2, 3, 4, and 5; and n4 is selected from the group consisting of 0, 1, 2, 3, and 4.
  3. 3 . The compound of claim 1 , wherein L is
  4. 4 . The compound of claim 1 , wherein L is
  5. 5 . The compound of claim 1 , wherein L is
  6. 6 . The compound of claim 1 , wherein L is
  7. 7 . A compound selected from the group consisting of: or a salt, solvate, enantiomer, or tautomer thereof.
  8. 8 . A pharmaceutical composition comprising the compound of claim 1 and at least one pharmaceutically acceptable carrier.
  9. 9 . The pharmaceutical composition of claim 8 , further comprising at least one additional agent that treats or ameliorates a cancer.
  10. 10 . The pharmaceutical composition of claim 9 , wherein the at least one additional agent comprises a MEK inhibitor, a BRAF inhibitor, or an immune checkpoint inhibitor.
  11. 11 . The composition of claim 9 , wherein the cancer is at least one selected from the group consisting of colorectal cancer, melanoma, drug-resistant BRAF mutant melanoma and non-small-cell lung cancer (NSCLC).
  12. 12 . A method of treating or ameliorating a cancer in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of claim 1 .
  13. 13 . A method of increasing or promoting immune cell infiltration or immune cell recruitment to a cancerous tumor in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of claim 1 .
  14. 14 . The method of claim 12 , wherein the compound is administered as a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier.
  15. 15 . The method of claim 12 , wherein at least one of the following applies: (a) the compound is the only therapeutically effective agent administered to the subject; (b) the compound is the only therapeutically effective agent administered to the subject in an amount that treats or ameliorates the cancer in the subject.
  16. 16 . The method of claim 12 , wherein the cancer is at least one selected from the group consisting of epithelial cancer, Merkel cell carcinoma, liver cancer, cervical cancer, anal cancer, penile cancer, vulvar cancer, vaginal cancer, breast cancer, ovarian cancer, uterine cancer, skin cancer, melanoma, oral cancer, colon cancer, neck cancer, head cancer, eye cancer, Kaposi's sarcoma, leukemia, nasopharyngeal carcinoma, mesothelioma, bone cancer, brain cancer, prostate cancer, testicular cancer, pancreatic cancer, hepatocellular carcinoma, lung cancer, and lymphoma.
  17. 17 . The method of claim 12 , wherein the cancer is at least one selected from the group consisting of colorectal cancer, melanoma, drug-resistant BRAF mutant melanoma and non-small-cell lung cancer (NSCLC).
  18. 18 . The method of claim 12 , wherein at least one of the following applies: (a) the subject is a mammal; (b) the compound is administered by an administration route selected from the group consisting of inhalational, oral, rectal, vaginal, parenteral, intracranial, topical, transdermal, pulmonary, intranasal, buccal, ophthalmic, intrathecal, and intravenous; (c) the subject is further administered at least one additional agent that treats or ameliorates the cancer.
  19. 19 . The method of claim 18 , wherein in (c) the at least one additional agent comprises a MEK inhibitor, a BRAF inhibitor, or an immune checkpoint inhibitor.
  20. 20 . The method of claim 19 , wherein the compound and the at least one additional agent are co-administered or co-formulated.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a 35 U.S.C. § 371 national phase application from, and claiming priority to, International Application No. PCT/US2021/024900, filed Mar. 30, 2021, which claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63/002,847, filed Mar. 31, 2020, all of which are incorporated herein by reference in their entireties. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under grant numbers R01 CA139319 and P01 CA114046 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND The chaperone heat shock protein 70 (HSP70, also HSPA1A) is the founding member of a family of proteins that function in the control of protein homeostasis, or proteostasis. There are over ten members of this family. Of these, HSP70 is the primary stress-induced member, while other family members like Hsc70, BiP and GRP75 are constitutively expressed and are not appreciably induced by stress. Unlike these other constitutively expressed family members, HSP70 is not required for life: HSP70 knockout mice are viable and fertile. In cancer cells HSP70 serves a cytoprotective role, protecting tumor cells from proteotoxicity induced by stresses such as oxidative stress and aneuploidy. Consistent with this, this protein is markedly overexpressed in human tumors, but is marginally or undetectably expressed in normal, non-transformed cells. In colorectal cancer, HSP70 overexpression is a significant marker of poor prognosis, particularly in late stage cancer. Along these lines, this chaperone plays a significant role in CRC incidence, as crossing APC-Min mice to HSP70 knockout mice dramatically reduces adenoma formation and improves survival. There is a need in the art for novel compounds and/or compositions that can be used to treat cancer, especially cancers overexpressing HSP70. The present disclosure addresses these unmet needs. SUMMARY OF THE DISCLOSURE In one aspect, the present disclosure related to a compound of formula (I), or a salt, solvate, enantiomer, and/or tautomer thereof: BINDER-X—(Z1)m1—Y—(Z2)m2-L  (I), wherein: BINDER, L, X, Y, Z1, Z2, m1, and m2 are described elsewhere herein. In certain embodiments, the compound of formula (I) is selected from the group consisting of: In another aspect, the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) and at least one pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition further comprises at least one additional agent that treats, ameliorates, and/or prevents a cancer. In certain embodiments, the at least one additional agent comprises a MEK inhibitor, a BRAF inhibitor, or an immune checkpoint inhibitor. In certain embodiments, the cancer is at least one selected from the group consisting of colorectal cancer, melanoma, drug-resistant BRAF mutant melanoma and non-small-cell lung cancer (NSCLC). In another aspect, the present disclosure relates to a method of treating, ameliorating, and/or preventing a cancer in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of a compound of formula (I) and/or a pharmaceutical composition comprising a compound of formula (I) and at least one pharmaceutically acceptable carrier. In certain embodiments, the compound is administered as a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier. In certain embodiments, the compound is the only therapeutically effective agent administered to the subject. In certain embodiments, the compound is the only therapeutically effective agent administered to the subject in an amount that treats, ameliorates, and/or prevents the cancer in the subject. In certain embodiments, the cancer is at least one selected from the group consisting of epithelial cancer, Merkel cell carcinoma, liver cancer, cervical cancer, anal cancer, penile cancer, vulvar cancer, vaginal cancer, breast cancer, ovarian cancer, uterine cancer, skin cancer, melanoma, oral cancer, colon cancer, neck cancer, head cancer, eye cancer, Kaposi's sarcoma, leukemia, nasopharyngeal carcinoma, mesothelioma, bone cancer, brain cancer, prostate cancer, testicular cancer, pancreatic cancer, hepatocellular carcinoma, lung cancer, and lymphoma. In certain embodiments, cancer is at least one selected from the group consisting of colorectal cancer, melanoma, drug-resistant BRAF mutant melanoma and non-small-cell lung cancer (NSCLC). In certain embodiments, the subject is a mammal. In certain embodiments, the compound is administered by an administration route selected from the group consisting of inhalational, oral, rectal, vaginal, parenteral, intracranial, topical, transdermal, pulmonary, intranasal, buccal, ophthalmic, intrathecal, and intravenous. In certain embodiments, the subject is fur