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US-20260125367-A1 - CANCER TREATMENTS TARGETING CANCER STEM CELLS

US20260125367A1US 20260125367 A1US20260125367 A1US 20260125367A1US-20260125367-A1

Abstract

Disclosed are compounds, methods, compositions, and kits that allow for treating cancer by, e.g., targeting cancer stem cells. In some embodiments, the cancer is colorectal cancer, gastric cancer, gastrointestinal stromal tumor, ovarian cancer, lung cancer, breast cancer, pancreatic cancer, prostate cancer, testicular cancer, or lymphoma. In some embodiments, the cancer is liver cancer, endometrial cancer, leukemia, or multiple myeloma. The compounds utilized in the disclosure are of Formula (0), (O′), and (I):

Inventors

  • Gregory Thomas Crimmins
  • Dennise Alexandra De Jesús Diaz
  • Yushma BHURRUTH-ALCOR

Assignees

  • REMEDY PLAN, INC.

Dates

Publication Date
20260507
Application Date
20251105

Claims (20)

  1. 1 - 112 . (canceled)
  2. 113 . A compound of the formula: or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein: R 1 is substituted or unsubstituted, C 1-6 alkyl; R 2 is substituted or unsubstituted, C 1-6 alkyl; R 3 is hydrogen, halogen, substituted or unsubstituted, C 1-6 alkyl, —OR a , —N(R a ) 2 , or —CN; each instance of R 4 is independently hydrogen, halogen, substituted or unsubstituted, C 1-6 alkyl, —OR a , —N(R a ) 2 , or —CN; each instance of R 5 is independently hydrogen, halogen, substituted or unsubstituted, C 1-6 alkyl, —OR a , —N(R a ) 2 , or —CN; each instance of R a is independently hydrogen, substituted or unsubstituted, C 1-6 alkyl, an oxygen protecting group when attached to an oxygen atom, or a nitrogen protecting group when attached to a nitrogen atom; each R 6 is independently hydrogen, substituted or unsubstituted, C 1-6 alkyl, substituted or unsubstituted, C 2-6 alkenyl, substituted or unsubstituted, C 2-6 alkynyl, substituted or unsubstituted, 3- to 13-membered, monocyclic or bicyclic carbocyclyl, substituted or unsubstituted, 3- to 13-membered, monocyclic or bicyclic heterocyclyl, substituted or unsubstituted, 6- to 11-membered, monocyclic or bicyclic aryl, substituted or unsubstituted, 5- to 11-membered, monocyclic or bicyclic heteroaryl, or a nitrogen protecting group; R 7 is substituted or unsubstituted pyridinyl; and each instance of R 8 is independently hydrogen, halogen, substituted or unsubstituted, C 1-6 alkyl, —OR a , —N(R a ) 2 , or —CN.
  3. 114 . The compound of claim 113 , wherein R 1 is unsubstituted C 1-6 alkyl.
  4. 115 . The compound of claim 113 , wherein R 2 is unsubstituted C 1-3 alkyl.
  5. 116 . The compound of claim 113 , wherein R 3 is halogen, substituted or unsubstituted, C 1-6 alkyl, or —OR a .
  6. 117 . The compound of claim 113 , wherein each instance of R 4 is hydrogen.
  7. 118 . The compound of claim 113 , wherein each instance of R 5 is hydrogen.
  8. 119 . The compound of claim 113 , wherein R 6 is hydrogen.
  9. 120 . The compound of claim 113 , wherein each instance of R 8 is hydrogen.
  10. 121 . The compound of claim 113 , wherein R 7 is unsubstituted 3-pyridinyl.
  11. 122 . The compound of claim 113 , wherein R 7 is substituted 3-pyridinyl.
  12. 123 . The compound of claim 113 , wherein R 7 is wherein each instance of R 9 is independently hydrogen, halogen, substituted or unsubstituted, C 1-6 alkyl, —OR a , —N(R a ) 2 , or —CN.
  13. 124 . The compound of claim 113 , wherein R 7 is wherein R 9 is hydrogen, halogen, substituted or unsubstituted, C 1-6 alkyl, —OR a , —N(R a ) 2 , or —CN.
  14. 125 . The compound of claim 113 , wherein R 7 is wherein R 9 is hydrogen, halogen, substituted or unsubstituted, C 1-6 alkyl, —OR a , —N(R a ) 2 , or —CN.
  15. 126 . The compound of claim 113 , wherein the compound is a compound appearing in Table A, paragraph [0205], or Table 5.
  16. 127 . A pharmaceutical composition comprising a compound of claim 113 , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof, and a pharmaceutically acceptable excipient.
  17. 128 . The pharmaceutical composition of claim 127 , wherein the composition further comprises an additional pharmaceutical agent.
  18. 129 . A method of treating cancer comprising administering to a subject a therapeutically effective amount of a compound of claim 113 , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.
  19. 130 . The method of claim 129 , wherein: (a) the cancer comprises cancer stem cells; and/or (b) the cancer is: (i) gastric cancer; (ii) gastrointestinal stromal tumor; (iii) ovarian cancer; (iv) lung cancer; (v) breast cancer; (vi) pancreatic cancer; (vii) prostate cancer; (viii) gastric cancer subtype GS or gastric cancer subtype CIN; (ix) colorectal cancer; (x) colorectal cancer subtype CMS2 or colorectal cancer subtype CMS4; (xi) testicular cancer; (xii) liver cancer (xiii) endometrial cancer; (xiv) lymphoma; (xv) B-cell lymphoma; (xvi) large cell immunoblastic lymphoma; (xvii) leukemia; (xviii) chronic myelocytic leukemia (CML); (xix) chronic lymphocytic leukemia; (xx) acute lymphoblastic leukemia; (xxi) multiple myeloma; (xxii) uterine cancer; (xxiii) non-Hodgkin's lymphoma; (xxiv) large B-cell lymphoma; (xxv) Burkitt's B-cell lymphoma; (xxvi) acute monocytic leukemia; (xxvii) acute lymphocytic leukemia; (xxviii) B-cell acute lymphocytic leukemia; (xxix) B-cell acute lymphoblastic leukemia; (xxx) T-cell acute lymphoblastic leukemia; or (xxxi) B-cell myeloma.
  20. 131 . A method comprising contacting a cell with an effective amount of a compound of claim 113 , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

Description

RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Applications, U.S. Ser. No. 62/667,412, filed May 4, 2018, and U.S. Ser. No. 62/815,251, filed Mar. 7, 2019, each of which is incorporated herein by reference. BACKGROUND OF THE INVENTION Cancer is ubiquitous and despite medical advanced, remains among the leading cause of death worldwide. In 2017, an estimated 1.7 million new cases of cancer were diagnosed and 600,000 people died from the disease.1 Cancer is the second leading cause of death globally and nearly 1 in 6 deaths is due to cancer. The number of new cases is expected to rise by about 70% over the next 2 decades. The economic impact of cancer is significant and is increasing. The total annual economic cost of cancer in 2010 was estimated at approximately 1.16 trillion US dollars.2 Cancer is a generic term for a large group of diseases that can affect any part of the body. Other terms used are malignant tumors and neoplasms. Cancer arises from the transformation of normal cells into tumor cells in multistage process that generally progresses from a pre-cancerous lesion to a malignant tumor. One defining feature of cancer is the rapid creation of abnormal cells that grow beyond their usual boundaries, and which can then invade adjoining parts of the body and spread to other organs, the latter process referred to as metastasizing. Metastases are a major cause of death from cancer. The most common cause of cancer death are cancers of lung, liver, colorectal, stomach, and breast. While there has been some progress in treating subsets of cancer types, the average cancer death rate is still extremely high, with little overall improvement in the ongoing cancer crisis. Nearly all modern cancer treatments, including chemotherapy, targeted therapy, and immunotherapy, focus on de-bulking tumors without targeting the most dangerous cells in the tumor: cancer stem cells. Cancer stem cells are responsible for the spread of cancer cells throughout the body, the growth of tumors, cancer's resistance to chemotherapy, and the recurrence of tumors after treatment or surgical removal.3,4 Because current treatments do not target the cancer stem cell population, they frequently lead to the rise of resistant tumors and continued cancer spread. SUMMARY OF THE INVENTION The discovery of cancer stem cells provides an opportunity to merge the fields of oncology and embryonic stem cell biology.5,6 By targeting what makes cancer so dangerous—the embryonic properties of cancer stem cells that form the basis for cancer growth, spread, and resistance—the development of effective and non-toxic therapies can be achieved via a strategy called cancer containment therapy. Therapies that can both diminish tumor bulk and disrupt cancer stem cells will revolutionize cancer treatment.7 Described herein are compounds that force differentiation of cancer stem cells, inhibiting the signaling pathways required for metastasis, which are the same pathways used by embryonic stem cells during differentiation and development.8,9 These properties can be safely targeted because they only occur in embryonic stem cells and not healthy adult tissue. These compounds will be more effective than traditional cancer treatments in decreasing tumor growth, prolonging life, and preventing metastasis and recurrence. And because the reactivation of embryonic properties is a property shared by many kinds of tumors, cancer containment therapy is expected to be effective on many different types of cancer, including cancer of the colon, stomach, prostate, testicles, and breast. Compounds, methods, compositions, uses, and kits that allow for treating proliferative diseases, benign neoplasms, and cancer are disclosed herein. In one aspect, the compounds of the disclosure are of Formula (0): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the variables recited in Formula (0) are as described herein. In another aspect, the present disclosure provides methods for treating cancer comprising administering to a subject a therapeutically effective amount of a compound of Formula (0), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the variables recited in Formula (0) are as described herein. In one aspect, the compounds of the disclosure are of Formula (0′): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the variables recited in Formula (0′) are as described herein. In another aspect, the present disclosure provides methods for treating cancer comprising administering to a subject a therapeutically effective amount of a compound of Formula (0′), or a pharmaceutically acceptable sal