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US-12622892-B2 - Methods for treating endometriosis

US12622892B2US 12622892 B2US12622892 B2US 12622892B2US-12622892-B2

Abstract

Methods of treating endometriosis through modulation of Nuclear Receptor Subfamily 4 Group A Member 1 (NR4A1) activity including administration of an NR4A1 ligand to an individual in need thereof are described. In an embodiment, the compounds include methylene substituted diindolylmethanes.

Inventors

  • Stephen Safe
  • Kumaravel Mohankumar

Assignees

  • THE TEXAS A&M UNIVERSITY SYSTEM

Dates

Publication Date
20260512
Application Date
20210224

Claims (20)

  1. 1 . A method of treating endometriosis in an individual by antagonization of Nuclear Receptor Subfamily 4 Group A Member 1 (NR4A1) activity, the method comprising administering to the individual a therapeutically effective amount of a compound of the formula: or a salt thereof, wherein, R 1 , R 2 , R 1 ′, and R 2 ′ are each independently selected from the group consisting of hydrogen, a linear alkyl group containing one to about ten carbon atoms, and a branched alkyl group containing one to about ten carbon atoms; R 3 , R 4 , R 5 , R 6 , R 3 ′, R 4 ′, R 5 ′, and R 6 ′ are each independently selected from the group consisting of hydrogen, a halogen, a linear alkyl group containing one to about ten carbon atoms, a branched alkyl group containing one to about ten carbon atoms, an alkoxy group containing one to about ten carbon atoms, and a nitro group; R 7 is selected from the group consisting of hydrogen, a linear alkyl group containing one to about ten carbon atoms, a branched alkyl group containing one to about ten carbon atoms, a cycloalkyl group containing one to about ten carbon atoms, and an aryl group; R 8 , R 9 , R 10 , R 11 , and R 12 are independently selected from the group consisting of H, a halogen, a linear alkyl group containing one to about ten carbon atoms, a branched alkyl group containing one to about ten carbon atoms, an alkoxy group containing one to about ten carbon atoms, a haloalkyl group containing one to about ten carbon atoms, a nitro group, a hydroxyl group, and a haloalkoxy group containing one to about ten carbon atoms; wherein at least one of R 8 , R 9 , R 10 , R 11 , and R 12 is OH, and wherein when R 10 is OH at least one of R 8 , R 9 , R 11 , and R 12 is not hydrogen.
  2. 2 . The method of claim 1 , wherein R 8 is OH.
  3. 3 . The method of claim 2 , wherein R 9 , R 10 , R 11 , and R 12 are each H.
  4. 4 . The method of claim 2 , wherein R 9 , R 10 , R 11 , and R 12 are independently selected from the group consisting of a halogen, CH 3 , OCCl 3 , CF 3 , t-butyl, OCH 3 , OH, and C 6 H 5 .
  5. 5 . The method of claim 2 , wherein R 10 is OCH 3 .
  6. 6 . The method of claim 2 , wherein R11 is selected from the group consisting of CH 3 , OCH 3 , and CF 3 .
  7. 7 . The method of claim 2 , wherein R 9 and R 11 are Br.
  8. 8 . The method of claim 2 , wherein the compound is selected from the group consisting of: and salts thereof.
  9. 9 . The method of claim 1 , wherein R 9 is OH.
  10. 10 . The method of claim 9 , wherein R 8 , R 10 , R 11 , and R 12 are each H.
  11. 11 . The method of claim 9 , wherein R 8 , R 10 , R 11 , and R 12 are independently selected from the group consisting of a halogen, CH 3 , OCCl 3 , CF 3 , t-butyl, OCH 3 , OH, and C 6 H 5 .
  12. 12 . The method of claim 9 , wherein R 8 is a halogen.
  13. 13 . The method of claim 9 , wherein the compound is selected from the group consisting of: and salts thereof.
  14. 14 . The method of claim 1 , wherein R 10 is OH.
  15. 15 . The method of claim 14 , wherein R 8 , R 9 , R 11 , and R 12 are independently selected the group consisting of a halogen, CH 3 , OCCl 3 , CF 3 , t-butyl, OCH 3 , OH, and C 6 H 5 .
  16. 16 . The method of claim 14 , wherein R 9 is a halogen and R 11 is selected from the group consisting of H, a halogen, and OCH 3 .
  17. 17 . The compound of claim 14 , wherein the compound is selected from the group consisting of: and salts thereof.
  18. 18 . The method of claim 1 , wherein antagonization of NR4A1 induces down-regulation of a protein selected from the group consisting of EFGR, cMyc, survivin, Bcl-2, SMA, and combinations thereof.
  19. 19 . The method of claim 1 , wherein antagonization of NR4A1 activity induces up-regulation of Bax.
  20. 20 . The method of claim 1 , wherein antagonization of NR4A1 activity induces decreased levels of mRNA of fibrosis markers selected from the group consisting of FN, Col1A1, CTGF, and combinations thereof.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS The present application is a National Stage of International Application No. PCT/US2021/019402, filed on Feb. 24, 2021, which claims the benefit of U.S. Provisional Application No. 62/981,431, filed on Feb. 25, 2020, the content of each of which is incorporated herein by reference in its entirety. STATEMENT OF GOVERNMENT LICENSE RIGHTS This invention was made with Government support under P30-ES029067 awarded by National Institutes of Health. The Government has certain rights in the invention. BACKGROUND Endometriosis is a common but complex inflammatory disease that primarily affects women during their reproductive years, and it is estimated that 5,500,000 women in the United States and 176,000,000 women worldwide exhibit symptoms of endometriosis. Endometriosis develops when cells lining the uterus are implanted at distal sites which can include the pelvic area, peritoneal surfaces, ovaries, ligaments, bowel, and bladder. Endometriosis originates, in part, from retrograde menstruation; resulting in endometriotic lesions, which are variable to their severity and pain and overall short term or chronic adverse health effects. Once diagnosed, the staging of the disease (i.e., stage I-IV) and its location are important for determining the appropriate treatment regimen which may include surgical removal of the endometriotic tissues and hormonal therapies which include progestins, oral contraceptives, and GnRH antagonists. There are serious concerns regarding the use of hormonal therapies for treating endometriosis in women of child-bearing age, and less toxic hormone-independent treatments need to be developed. There is presently an unmet need for a method of treating endometriosis that avoids or reduces the noted side effects of conventional hormone therapy treatments of endometriosis. The signaling pathways activated in endometriosis resemble those observed in cancer and include inflammatory-mediated responses associated with macrophage recruitment and activation, activation of growth-promoting and survival genes/pathways, and angiogenic/pro-migration genes/pathways. For example, mTOR signaling is activated in endometriosis. However, the use of mTOR inhibitors for treating this disease is limited due to toxicity concerns. The orphan nuclear receptors Nuclear Receptor Subfamily 4 Group A Member 1 (NR4A1) (such as according to SEQ ID NO. 1), Nuclear Receptor Subfamily 4 Group A Member 2 (NR4A2), and Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3) are immediate early genes induced by multiple stressors, and NR4A receptors play an important role in maintaining cellular homeostasis and disease. There is increasing evidence for the role of these receptors in metabolic, cardiovascular and neurological functions as well as in inflammation and inflammatory diseases and in immune functions and cancer. NR4A1 regulates cancer cell proliferation, survival, cell cycle progression, migration, and invasion in lung, melanoma, pancreatic, colon, cervical, ovarian, and gastric cancer, and Rhabdomyosarcoma cell lines and these responses are inhibited by bis-indole derived NR4A1 ligands that act as antagonists in cancer cells. There is also evidence that NR4A1 is overexpressed in endometriosis, and it was reported that after ultrasound-guided ethanol scleropathy in patients with high serum expression of NR4A1, levels of this receptor were significantly decreased after therapy. Levels of phosphorylated NR4A1 were higher in ovarian endometriotic tissue compared to normal endometrium; moreover, loss of NR4A1 stimulated fibrogenesis and activation of NR4A1 by the NR4A1 agonist cytosporone β suggested this receptor protected against fibrogenesis. Ishikawa endometrial cancer cells are frequently used as models for endometriotic epithelial cells, and our recent study clearly showed that NR4A1 exhibited pro-endometriotic activities that were inhibited by NR4A1 antagonists. SUMMARY The present disclosure provides such methods of treating endometriosis along with other related advantages. In this regard, the present disclosure demonstrates that NR4A1 regulates multiple pro-endometriotic genes/pathways that are inhibited by NR4A1 antagonists and, in an aspect, provides methods of treating endometriosis in an individual by modulation of Nuclear Receptor Subfamily 4 Group A Member 1 (NR4A1) activity, comprising administering to the individual a therapeutically effective amount of a compound of the present disclosure, such as an NR4A1 ligand. In an embodiment, the NR4A1 ligand has the formula: or a salt thereof,wherein,R1, R2, R1′, and R2′ are each independently selected from the group consisting of hydrogen, a linear alkyl group containing one to about ten carbon atoms, and a branched alkyl group containing one to about ten carbon atoms;R3, R4, R5, R6, R3′, R4′, R5′, and R6′ are each independently selected from the group consisting of hydrogen, a halogen, a linear alkyl group containing one to ab