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US-12624038-B2 - Molecules and methods related to treatment of uncontrolled cellular proliferation

US12624038B2US 12624038 B2US12624038 B2US 12624038B2US-12624038-B2

Abstract

The present disclosure relates to chemical compounds that modulate cellular proliferation for the treatment of uncontrolled cellular proliferation disorders (such as cancer), pharmaceutical compositions containing such compounds, and their use in treatment. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

Inventors

  • Jaeki Min
  • Jamie Jarusiewicz
  • Marcelo Actis
  • Yunchao Chang
  • Kathryn Roberts
  • Charles Mullighan
  • Zoran Rankovic

Assignees

  • ST. JUDE CHILDREN'S RESEARCH HOSPITAL

Dates

Publication Date
20260512
Application Date
20200730

Claims (19)

  1. 1 . A compound having a structure represented by a formula: wherein A is selected from —O—, —S—, —NH—, —CH 2 —, —O—(C1-C4 alkyl)-C(O) NH—, and a structure wherein L is selected from C2-C15 alkyl and —(CH 2 CH 2 O) n (C1-C4 alkyl)-; wherein n, when present, is selected from 1, 2, 3, 4, 5, 6, 7, and 8; wherein Q is a structure: wherein R 1 is selected from C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 cyanoalkyl, C1-C8 aminoalkyl, and a structure selected from: and wherein Ar 1 is a structure selected from: wherein X is selected from —C(O)— and —CH 2 ; wherein Z is selected from —CH 2 — and —C(O)—; wherein R 7 is selected from hydrogen and C1-C8 alkyl; wherein each of R 8a , R 8b , R 8c , and R 8d is independently selected from hydrogen, halogen, —NH 2 , —OH, —NO 2 , —CN, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4) (C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein each of R 9a , R 9b , R 9c , and R 9d , when present, is independently selected from hydrogen, halogen, —NH 2 , —OH, —NO 2 , —CN, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4) (C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.
  2. 2 . The compound of claim 1 , wherein A is selected from —NH— and —CH 2 —.
  3. 3 . The compound of claim 1 , wherein L is C2-C15 alkyl.
  4. 4 . The compound of claim 1 , wherein L is —(CH 2 CH 2 O) n (C1-C4 alkyl)-.
  5. 5 . The compound of claim 1 , wherein R 1 is C1-C8 alkyl.
  6. 6 . The compound of claim 1 , wherein Ar 1 is a structure represented by a formula:
  7. 7 . The compound of claim 1 , wherein Ar 1 is a structure represented by a formula:
  8. 8 . The compound of claim 1 , wherein Ar 1 is a structure:
  9. 9 . The compound of claim 1 , wherein Ar 1 is a structure represented by a formula:
  10. 10 . The compound of claim 1 , wherein Z is —C(O)—.
  11. 11 . The compound of claim 1 , wherein the compound is selected from: or a pharmaceutically acceptable salt thereof.
  12. 12 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.
  13. 13 . A method of treating a disorder of uncontrolled cellular proliferation in a subject, the method comprising the step of administering to the subject an effective amount of the compound of claim 1 .
  14. 14 . The method of claim 13 , wherein the subject has been diagnosed with a need for treatment of the disorder prior to the administering step.
  15. 15 . The method of claim 13 , further comprising the step of identifying a subject in need of treatment of the disorder.
  16. 16 . The method of claim 13 , wherein the effective amount is a therapeutically effective amount.
  17. 17 . The method of claim 13 , wherein the disorder is a cancer.
  18. 18 . The method of claim 17 , wherein the cancer is selected from a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma).
  19. 19 . The method of claim 17 , wherein the cancer is acute lymphoblastic leukemia (ALL).

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This Application is a national phase application under 35 U.S.C. § 371 of International Application No. PCT/US2020/044317, filed on Jul. 30, 2020, which claims the benefit of U.S. Application No. 62/881,774, filed on Aug. 1, 2019, the contents of which are hereby incorporated by reference in their entireties entirety. STATEMENT REGARDING FEDERALLY FUNDED RESEARCH This invention was made with government support under grant number CA197695 awarded by the National Institutes of Health. The government has certain rights in the invention. REFERENCE TO SEQUENCE LISTING The Sequence Listing submitted Jan. 21, 2022 as a text filed named “19116_0044U2_ST25.txt,” created on Jan. 20, 2022, and having a size of 1.279 bytes 1,235 bytes is hereby incorporated by reference pursuant to 37 C.F.R. § 1.52 (e)(5). BACKGROUND Cancer is a disease characterized primarily by an uncontrolled division of abnormal cells (uncontrolled cellular proliferation) derived from a given normal tissue and the invasion of adjacent tissues by these malignant cells. Blood or lymphatic transportation can spread cancer cells to other parts of the body leading to regional lymph nodes and to distant sites (metastasis). Cancer is a complex, multistep process that begins with minor preneoplastic changes, which may under certain conditions progress to neoplasia. There are more than 100 different types of cancer, which can be grouped into broader categories. The main categories include carcinoma, sarcoma, leukemia, lymphoma and myeloma, and central nervous system cancers. The incidence of cancer continues to climb as the general population ages, as new cancers develop, and as susceptible populations (e.g., people infected with AIDS or excessively exposed to sunlight) grow. A tremendous demand therefore exists for new methods and compositions that can be used to treat patients with cancer. Hematologic or hematopoietic malignancies are cancers of the blood or bone marrow, including leukemia and lymphoma. Leukemia is a type of cancer of the blood characterized by abnormal accumulation of immature white blood cells. There are four types of leukemia: acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML). Acute leukemia is a rapidly progressing disease that results in the accumulation of immature, functionless cells in the marrow and blood. The marrow often stops producing enough normal red cells, which include cells and platelets. On the other hand, chronic leukemia progresses more slowly and allows greater numbers of more mature, functional cells to be made. Leukemia can affect people at any age. The cause of most cases of leukemia is not known. Extraordinary doses of radiation and certain cancer therapies are possible causes. About 90% of leukemia cases are diagnosed in adults. Cases of chronic leukemia account for 4.5 percent more cases that acute leukemia. The dramatic improvement in blood cancer treatment in the latter part of the twentieth century is largely the result of chemotherapy. In addition, there are more than fifty drugs individually used to treat these disorders and a number of potential new therapies are under investigation in clinical trials. Thus, there remains a need for treat a disorder of uncontrolled cellular proliferation. The following disclosure describes a group of such compounds, as well as methods for making and using them. SUMMARY In accordance with the purpose(s) of the invention, as embodied and broadly described herein, the invention, in one aspect, relates to compositions and methods for use in the prevention and treatment of disorders associated with uncontrolled cellular proliferation, such as cancer. Disclosed are compounds having a structure represented by a formula: wherein A is selected from —O—, —S—, —NH—, —CH2—, —O—(C1-C4 alkyl)-C(O)NH—, and a structure wherein L is selected from C2-C15 alkyl and —(CH2CH2O)n(C1-C4 alkyl)-; wherein n is selected from 1, 2, 3, 4, 5, 6, 7, and 8; wherein Q is selected from —NHC(O)(C6H4)— and —C(O)NH(C6H4)—; wherein R1 is selected from C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 cyanoalkyl, C1-C8 aminoalkyl, and a structure selected from: and wherein Ar1 is a structure selected from: wherein X is selected from —C(O)— and —CH2—; wherein Z is selected from —CH2— and C(O); wherein R7 is selected from hydrogen and C1-C8 alkyl; wherein each of R8a, R8b, R8c, and R8d is independently selected from hydrogen, halogen, —NH2, —OH, —NO2, —CN, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein each of R9a, R9b, R9c, and R9d, when present, is independently selected from hydrogen, halogen, —NH2, —OH, —NO2, —CN, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylami