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WO 2016/170102 Al 27 October 2016 (27.10.2016) P O P C T

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WO 2016/170102 Al 27 October 2016 (27.10.2016) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/170102 Al 27 October 2016 (27.10.2016) P O P C T (51) International Patent Classification: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A61K 31/167 (2006.01) A61P 5/28 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61K 31/37 (2006.01) A61P 35/00 (2006.01) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, A61K 31/4166 (2006.01) KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (21) International Application Number: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, PCT/EP2016/058990 SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (22) International Filing Date: TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 22 April 2016 (22.04.2016) (84) Designated States (unless otherwise indicated, for every (25) Filing Language: English kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (26) Publication Language: English TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (30) Priority Data: TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, 15 164648.6 22 April 2015 (22.04.2015) EP DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (71) Applicant: CEMM - FORSCHUNGSZENTRUM FUR SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, MOLEKULARE MEDIZIN GMBH [AT/AT]; Lazar- GW, KM, ML, MR, NE, SN, TD, TG). ettgasse 14, AKH BT 25.3, 1090 Wien (AT). Declarations under Rule 4.17 : (72) Inventors: KUBICEK, Stefan; CeMM - Forschungszen- — as to applicant's entitlement to apply for and be granted a trum fur Molekulare Medizin GmbH, Lazarettgasse 14, patent (Rule 4.1 7(H)) AKH BT 25.3, 1090 Wien (AT). LICCIARDELLO, Marco; 34 Holcombe House, 52 Landor Road, London, Published: Greater London SW9 9NS (GB). — with international search report (Art. 21(3)) (74) Agent: VOSSIUS & PARTNER; Patentanwalte Rechtsan- — before the expiration of the time limit for amending the walte mbB, SiebertstraBe 3, 81675 Munchen (DE). claims and to be republished in the event of receipt of (81) Designated States (unless otherwise indicated, for every amendments (Rule 48.2(h)) kind of national protection available): AE, AG, AL, AM, — with sequence listing part of description (Rule 5.2(a)) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, o o (54) Title: COMBINATION OF AN ANTIANDROGEN WITH A VITAMIN K ANTAGONIST OR WITH A GAMMA -GLUTAMYL CARBOXYLASE INHIBITOR FOR THE THERAPY OF ANDROGEN RECEPTOR POSITIVE CANCER v (57) Abstract: The present invention relates to the combination of an antiandrogen with a vitamin K antagonist or with a γ-glutamyl o carboxylase inhibitor for use in the treatment or prevention of an androgen receptor positive cancer, such as prostate cancer, or a hy - peractive androgen receptor signaling disease/disorder. The invention also relates to a vitamin K antagonist or a γ-glutamyl carboxylase inhibitor for use in resensitizing an antiandrogen-resistant prostate cancer to the treatment with an antiandrogen. The in vention further provides a pharmaceutical composition comprising an antiandrogen, a vitamin K antagonist or a γ -glutamyl carboxylase inhibitor, and a pharmaceutically acceptable excipient. Combination of an antiandrogen with a vitamin K antagonist or with a γ -glutamyl carboxylase inhibitor for the therapy of androgen receptor positive cancer The present invention relates to the combination of an antiandrogen with a vitamin K antagonist or with a γ -glutamyl carboxylase inhibitor for use in the treatment or prevention of an androgen receptor positive cancer, such as prostate cancer, or a hyperactive androgen receptor signaling disease/disorder. The invention also relates to a vitamin K antagonist or a γ -glutamyl carboxylase inhibitor for use in resensitizing an antiandrogen-resistant prostate cancer to the treatment with an antiandrogen. The invention further provides a pharmaceutical composition comprising an antiandrogen, a vitamin K antagonist or a γ -glutamyl carboxylase inhibitor, and a pharmaceutically acceptable excipient. Drug discovery is a challenging process easily spanning 10-15 years (Paul SM et al., Nat Rev Drug Discov, 2010, 9:203-14). In spite of the recent advances in screening and sequencing technologies, the number of new molecular entities (NMEs) approved every year still hobbles below expectations (Mullard A , Nat Rev Drug Discov, 2014, 13:85-9; Scannell JW et al., Nat Rev Drug Discov, 2012, 11:191-200). Both industry and academia have tried to bypass the hurdles in the drug discovery process by repositioning clinical compounds for additional therapeutic indications, so-called drug repurposing (Ashburn TT et al., Nat Rev Drug Discov, 2004, 3:673-83). Patient diversity and drug resistance still represent significant obstacles in long-term pharmacological treatment of diseases such as cancer or infection (Holohan C et al., Nat Rev Cancer, 2013, 13:714-26; Clavel F et al., N Engl J Med, 2004, 350:1023-35). Multicomponent therapeutics have been shown to be an effective alternative in these circumstances (Bock C et al., Nat Rev Cancer, 2012, 12:494-501), providing a new strategy for more personalized medicine. Approved drugs proven to be safe, effective and bioavailable with their well-defined targets and mechanisms of action are an ideal starting points for generating new multicomponent regimes, and provide a fast-track to new clinical applications. These unique features have prompted academic efforts to embark on the challenge of cataloguing and collecting all drugs approved for human or veterinary use (Chong CR et al., Nat Chem Biol, 2006, 2:415-6; Huang R et al., Sci Transl Med, 201 1, 3:80ps16). However, access to these comprehensive libraries is limited to scientists affiliated to corresponding institutions or to external collaborators when screenings are performed on site. Moreover, a systematic pairwise combinatorial high-throughput screen (HTS) of all 14,814 molecules currently in the NCGC pharmaceutical collection (Huang R et al., Sci Transl Med, 201 1, 3:80ps16) would generate more than 100 million data points, an effort beyond the capacity of screening facilities. Smaller libraries containing between 780 and 1600 approved drugs are commercially available, however they do not cover all drug classes. In the context of the present invention, a set of representative FDA-approved drugs was computationally derived and used to generate a collection that optimally captures the chemical and biological diversity of all clinical compounds while fitting to a single 384-well screening plate. This collection was annotated with reported human maximum plasma concentrations to encourage HTS at pharmacologically relevant doses. Moreover, for all substances administered as prodrugs the respective active form was included. This collection of clinical compounds was named the CeMM Library of Unique Drugs (CLOUD). The non-redundant nature of this library allows for the systematic investigation of all combinations of CLOUD compounds. In a combinatorial HTS using the CLOUD library, it was surprisingly found that antiandrogens such as flutamide interact with vitamin K antagonists such as phenprocoumon to effect a synergistically enhanced inhibition of androgen receptor (AR) signaling, as further described in the appended examples. Androgen receptor signaling is known to play a crucial role in the pathogenesis of prostate cancer and is also involved in the development of other androgen receptor positive cancers (Chen Y et al., Lancet Oncol, 2009, 10:981-91 ; Mills IG, Nat Rev Cancer, 2014, 14:187-98; Taplin ME, Nat Clin Pract Oncol, 2007, 4:236-44; Wirth MP et al., Eur Urol, 2007, 5 1(2):306- 13). Further diseases/disorders involving hyperactive androgen receptor signaling include, e.g., hyperandrogenism (Ibanez L et al., J Clin Endocrinol Metab, 2003, 88:3333-3338), spinal- bulbar muscular atrophy (Matsumoto T et al., Annu Rev Physiol, 2013, 75:201-224), benign prostatic hyperplasia (Izumi K et al., Am J Pathol, 2013, 182:1942-1949), hypersexuality, paraphilia (Guay DR, Clin Ther, 2009, 3 1:1-31), acne, seborrhea, hirsutism (Lai JJ et al., Arch Dermatol Res, 2013, 304:499-510), androgenic alopecia, hidradenitis suppurativa, and polycystic ovary syndrome (Lin et al., Int J Gynaecol Obstet, 2013, 120:1 15-1 18). The inhibition of androgen receptor signaling with antiandrogens that antagonize the androgen receptor has been used or proposed for the treatment of such conditions. The synergistically enhanced inhibition of androgen receptor signaling which is achieved by the combination of an antiandrogen and a vitamin K antagonist in accordance with the present invention thus provides an improved therapy of androgen receptor positive cancer, including in particular prostate cancer, as well as hyperactive androgen receptor signaling diseases/disorders. The androgen receptor normally resides in the cytoplasm bound to chaperones such as HSP90 (Brinkmann AO et al., J Steroid Biochem Mol Biol, 1999, 69:307-13). Upon binding of dihydrotestosterone (DHT) the androgen receptor changes its conformation and translocates to the nucleus, where it binds androgen responsive elements (AREs) driving the transcription of canonical targets such as KLK3 (also known as prostate specific antigen PSA), TMPRSS2 and KLK2 (Tran C et al., Science, 2009, 324:787-90; Murtha P et al., Biochemistry (Mosc), 1993, 32:6459-64). Flutamide is a non-steroidal antiandrogen approved for the treatment of prostate cancer (Chen Y et al, Lancet Oncol, 2009, 10:981-91), acting as a DHT-competitive AR antagonist (Liao S et al., Endocrinology, 1974, 94:1205-9).
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