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W O 2019/232146 Al 05 December 2019 (05.12.2019) W IPO I PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property (1) Organization11111111111111111111111I1111111111111i1111liiiii International Bureau (10) International Publication Number (43) International Publication Date W O 2019/232146 Al 05 December 2019 (05.12.2019) W IPO I PCT (51) International Patent Classification: JIANG, Zaoli; 20 Cedar Rock Road, Woodbridge, Con A61K31/19(2006.01) A61K45/00(2006.01) necticut06525(US). A61K38/12 (2006.01) A61K 45/08 (2006.01) (74) Agent: DOYLE, Kathryn et al.; Saul Ewing Arnstein & (21) International Application Number: Lehr LLP, 1500 Market Street, 38th Floor, Philadelphia, PCT/US2019/034548 Pennsylvania 19102 (US). (22) International Filing Date: (81) Designated States (unless otherwise indicated, for every 30 May 2019 (30.05.2019) kind ofnational protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, (25)FilingLanguage: English CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, (26) Publication Language: English DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (30)PriorityData: HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, (30)/Priority : 01 June 2018 (01.06.2018) us KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (71) Applicant: YALE UNIVERSITY [US/US]; Two Whitney OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, Avenue, New Haven, Connecticut 06510 (US). SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, ZA, ZM, ZW. (72) Inventors: CHENG, YungChi; 961 BaldwinRoad, Wood- TR, TT, TZ, UA, UG, US, UZ, VC, VN, bridge, Connecticut 06525 (US). LAM, Wing; 470 Prospect (84) Designated States (unless otherwise indicated, for every Street, Apt. 38, New Haven, Connecticut 06511 (US). kind of regionalprotection available): ARIPO (BW, GH, (54) Title: COMPOSITIONS AND METHODS FOR TREATING STEROID HORMONE-RELATED DISEASES OR DISORDERS FIG. 1 + Y9 1.00 + Y1830 +Y1 831 0.75 0.5 -4--- .... 0 100 200 300 400 500 (57) Abstract: The invention relates in one aspect to the unexpected discovery that herbal extracts of the Rubia cordifolia plant are CA potent inhibitors of a range of receptors, proteins and enzymes implicated in the pathology of a number of common diseases and disorders. In certain embodiments, the method is useful for treating at least one disease or disorder related to a steroid hormone receptor including prostate cancer, breast cancer, ovarian cancer, lung cancer, leukemia and lymphoma. In other embodiments, the method is useful for treating at least one disease or disorder related to the expression of at least one protein selected from the group consisting of Brd4, Brd2, cyclin D1, p53, Gata3 and CD47. W O 20 19/232 146 Al l 1|||||||||||||||||||||||||||||||||111||||||||||||||||||||||||||||||||||||||| GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, Fl, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Declarations under Rule 4.17: - ofinventorship (Rule 4.17(iv)) Published: - with international search report (Art. 21(3)) - with sequence listing part of description (Rule 5.2(a)) WO 2019/232146 PCT/US2019/034548 TITLE OF THE INVENTION Compositions and Methods for Treating Steroid Hormone-Related Diseases or Disorders 5 CROSS-REFERENCE TO RELATED APPLICATIONS The present application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 62/679,386, filed June 1, 2018, which is hereby incorporated by reference herein in its entirety. 10 BACKGROUND OF THE INVENTION Progesterone, estrogen, androgen, and glucocorticoid receptors belong to a broad class of steroid hormone receptors. Steroid hormone receptors are ligand-dependent intracellular transcription factors that have been shown to influence the development and growth of a variety of cancers, including, but not limited to, prostate cancer, breast cancer, ovarian cancer, lung 15 cancer, leukemia and lymphoma. Hormonal therapies have shown promise in treating these kinds of cancers by modulating steroid hormone receptor activity. These results suggest that modulating steroid hormone receptor activity can be a potential target in the treatment of various cancers and other hormone receptor related diseases and disorders. There remains an unmet need in the art for novel compositions and methods for the 20 treatment of steroid hormone receptor related diseases and/or disorders. The present invention satisfies this unmet need. BRIEF SUMMARY OF THE INVENTON The invention provides a method of treating at least one disease or disorder in a subject. 25 In certain embodiments, the method comprises administering to the subject a therapeutically effective amount of an herbal extract of Rubia cordifolia or a fraction thereof In certain embodiments, the method comprises administering to the subject any active chemical species present in the herbal extract of Rubia cordifolia or the fraction thereof In certain embodiments, the at least one disease or disorder is related to the activity of at 30 least one steroid hormone receptor or the expression of at least one protein selected from the 1 WO 2019/232146 PCT/US2019/034548 group consisting of Brd4, Brd2, cyclin D1, p53, Gata3, Poly[ADP-ribose] polymerase-1 (PARP 1), and CD47. In certain embodiments, the active chemical species present in the herbal extract is selected from the group consisting of 1,3,6-Trihydroxy-2-methyl-9,10-anthracenedione 3-0-[a 5 L-Rhamnopyranosyl-(1--2)-6-0-acetyl-3-D-glucopyranoside] (RGA), 3,6-Trihydroxy-2-methyl 9,10-anthracenedione 3-0-[a-L-Rhamnopyranosyl-(1--2)--D-glucopyranoside] (RG) and salts, solvates, isomers, tautomers or prodrugs thereof OH 0O 0 OH OOOHOHO HO O OH HO 0 OH O 0 0 00 HO OH HO OH OH (RGA) OH (RG). 10 In certain embodiments, the herbal extract or the fraction thereof comprises RGA or salts, solvates, isomers, tautomers or prodrugs thereof In certain embodiments, the herbal extract or the fraction thereof further comprises RG or salts, solvates, isomers, tautomers or prodrugs thereof In certain embodiments, the at least one steroid hormone receptor is at least one selected 15 from the group consisting of progesterone receptors, estrogen receptors, androgen receptors, and glucocorticoid receptors. In certain embodiments, the at least one disease or disorder related to the activity of at least one steroid hormone receptor is a cancer selected from the group consisting of prostate cancer, breast cancer, ovarian cancer, lung cancer, uterine cancer, pancreatic cancer, colon 20 cancer, hepatocellular carcinoma, glioblastoma, multiple myeloma, NUT carcinoma, leukemia, and lymphoma. In certain embodiments, the cancer is a treatment resistant cancer selected from the group consisting of castration resistant prostate cancer, enzalutamide resistant prostate cancer, glucocorticoid receptor mediated resistant prostate cancer, BRCA1 (double strand break repair) 25 deficiency cancer, double negative breast cancer, and triple negative breast cancer. 2 WO 2019/232146 PCT/US2019/034548 In certain embodiments, the at least one disease or disorder related to the activity of at least one steroid hormone receptor is selected from the group consisting of prostate hyperplasia, Cushing's syndrome, androgenetic alopecia, acne, seborrhea, hirsutism (excessive body hair), hidradenitis suppurativa, sexual dysfunction, precocious puberty (in both males and females), 5 polycystic ovary syndrome, mastodynia (breast pain/tenderness), breast fibroids, mammoplasia (breast enlargement), macromastia (breast hypertrophy), gynecomastia, melasma, menorrhagia, endometriosis, endometrial hyperplasia, adenomyosis, uterine fibroids, and posttraumatic stress disorder (PTSD). In certain embodiments, the at least one disease or disorder related to expression of the at 10 least one protein is selected from the group consisting of Huntington's disease, schizophrenia, psoriasis, mantle cell lymphoma, breast carcinoma, bladder cancer, pituitary adenomas, parathyroid adenoma, pancreatic carcinoma, head and neck squamous cell carcinomas, and non small cell lung cancers. In certain embodiments, the method downregulates the expression of at least one protein 15 selected from the group consisting of Brd4, Brd2, cyclin D1, p53, Gata3, Poly[ADP-ribose] polymerase-1 (PARP-1), and CD47. In certain embodiments, the administration inhibits hyperacetylation of histone H3 in the subject. In certain embodiments, the administration promotes the phagocytosis of cancerous 20 tumor cells in the subject. In certain embodiments, the administration inhibits indoleamine-pyrrole 2,3-dioxygenase (IDO) activity in the subject. In certain embodiments, the subject is further administered at least one immune checkpoint inhibitor. In certain embodiments, the at least one immune checkpoint inhibitor is 25 selected from the group consisting of an anti-PD1, an anti-PD-Li, and an anti-CTLA4. In certain embodiments, the at least one immune checkpoint inhibitor is selected from the group consisting of Ipilimumab, Avelumab, Pembrolizumab, Nivolumab, Durvalumab, and Atezolizumab. In certain embodiments, the subject is a mammal. 30 In certain embodiments, the subject is human. 3 WO 2019/232146 PCT/US2019/034548 BRIEF DESCRIPTION OF THE DRAWINGS For the purpose of illustrating the invention, depicted in the drawings are
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