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(51) International Patent Classification: A61K 47/64 (20 .0 ) (21

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(51) International Patent Classification: A61K 47/64 (20 .0 ) (21 ( (51) International Patent Classification: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, A61K 47/64 (20 .0 ) TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (21) International Application Number: (84) Designated States (unless otherwise indicated, for every PCT/US2019/015733 kind of regional protection available) . ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (22) International Filing Date: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 29 January 2019 (29.01.2019) TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (25) Filing Language: English 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, SM, (26) Publication Language: English TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, (30) Priority Data: KM, ML, MR, NE, SN, TD, TG). 62/623,845 30 January 2018 (30.01.2018) US 62/653,285 05 April 2018 (05.04.2018) US Declarations under Rule 4.17: 62/688,309 2 1 June 2018 (21.06.2018) US — of inventorship (Rule 4.17(iv)) (71) Applicant: FOGHORN THERAPEUTICS INC. Published: [US/US]; 100 Binney Street, Suite 610, Cambridge, MA — with international search report (Art. 21(3)) 02142 (US). — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of (72) Inventors: ZHOU, Qianhe; c/o Foghorn Therapeutics Inc., amendments (Rule 48.2(h)) 100 Binney Street, Suite 610, Cambridge, MA 02142 (US). BOCKER, Michael; c/o Foghorn Therapeutics Inc., 100 Binney Street, Suite 610, Cambridge, MA 02142 (US). MILLAN, David, Simon; c/o Foghorn Therapeutics Inc., 100 Binney Street, Suite 610, Cambridge, MA 02142 (US). CHAN, Ho, Man; c/o Foghorn Therapeutics Inc., 100 Binney Street, Suite 610, Cambridge, MA 02142 (US). SOARES, Luis; c/o Foghorn Therapeutics Inc., 100 Binney Street, Suite 610, Cambridge, MA 02142 (US). NETHER- TON, Matthew, Russell; c/o Foghorn Therapeutics Inc., 100 Binney Street, Suite 610, Cambridge, MA 02142 (US). RUPPEL, Sabine, K.; c/o Foghorn Therapeutics Inc., 100 Binney Street, Suite 610, Cambridge, MA 02142 (US). YANG, Zhaoxia; c/o Foghorn Therapeutics Inc., 100 Bin¬ ney Street, Suite 610, Cambridge, MA 02142 (US). LOWE, Jason, T.; c/o Foghorn Therapeutics Inc., 100 Binney Street, Suite 610, Cambridge, MA 02142 (US). BRU- CELLE, Francois; c/o Foghorn Therapeutics Inc., 100 Bin¬ ney Street, Suite 610, Cambridge, MA 02142 (US). (74) Agent: ELBING, Karen, L. et al.; Clark & Elbing LLP, 101 Federal Street, 15th Floor, Boston, MA 021 10 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, 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, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (54) Title: METHODS AND COMPOUNDS FOR TREATING DISORDERS (57) Abstract: The present invention relates to methods and compositions for the treatment of BAF -related disorders such as cancers and viral infections. METHODS AND COMPOUNDS FOR TREATING DISORDERS Background Disorders can be affected by the BAF complex. BRD9 is a component of the BAF complex. The present invention relates to useful methods and compositions for the treatment of BAF-related disorders, such as cancer and infection. Summary of the Invention Bromodomain-containing protein 9 (BRD9) is a protein encoded by the BRD9 gene on chromosome 5 . BRD9 is a component of the BAF (BRG1- or BRM-associated factors) complex, a SWI/SNF ATPase chromatin remodeling complex, and belongs to family IV of the bromodomain- containing proteins. BRD9 is present in several SWI/SNF ATPase chromatin remodeling complexes and is upregulated in multiple cancer cell lines. Accordingly, agents which reduce the levels and/or activity of BRD9 may provide new methods for the treatment of disease and disorders, such as cancer. The inventors have found that depleting BRD9 in cells results in the depletion of the SS18-SSX fusion protein in those cells. The SS18-SSX fusion protein has been detected in more than 95% of synovial sarcoma tumors and is often the only cytogenetic abnormality in synovial sarcoma. Thus, agents that degrade BRD9, e.g., antibodies, enzymes, polynucleotides, and compounds, are useful in the treatment of cancers related to BRD9 or SS18-SSX expression such as soft tissue sarcomas, e.g., synovial sarcoma. The present disclosure features useful methods to treat cancer, e.g., in a subject in need thereof. In some embodiments, the methods described herein are useful in the treatment of disorders associated with BRD9 expression, e.g., adult soft tissue sarcomas. In some embodiments, the methods described herein are useful in the treatment of disorders associated with SS18-SSX fusion protein. In one aspect, the invention features a method of treating adult soft tissue sarcoma in a subject in need thereof, the method including administering to the subject an effective amount of an agent that reduces the level and/or activity of BRD9 in the sarcoma. In another aspect, the invention features a method of treating adult soft tissue sarcoma in a subject in need thereof, the method including administering to the subject an effective amount of an agent that reduces the level and/or activity of a BAF complex (e.g., GBAF) in the sarcoma. In another aspect, the invention features a method of reducing tumor growth of an adult soft tissue sarcoma in a subject in need thereof, the method including administering to the subject an effective amount of an agent that reduces the level and/or activity of BRD9 in the tumor. In another aspect, the invention features a method of inducing apoptosis in an adult soft tissue sarcoma cell, the method including contacting the cell with an effective amount of an agent that reduces the level and/or activity of BRD9 in the cell. In another aspect, the invention features a method of reducing the level of BRD9 in an adult soft tissue sarcoma cell, the method including contacting the cell with an effective amount of an agent that reduces the level and/or activity of BRD9 in the cell. In some embodiments of any of the above aspects, the adult soft tissue sarcoma cell is in a subject. In some embodiments, the subject or cell has been identified as expressing SS18-SSX fusion protein or BRD9 fusion protein. In another aspect, the invention features a method of modulating the level of an SS1 8-SSX fusion protein, SS1 8 wild-type protein, or SSX wild-type protein in a cell or subject, the method including contacting the cell with an effective amount of an agent that reduces the level and/or activity of BRD9 in a cell or subject. In some embodiments, the cell is in a subject. In another aspect, the invention features a method of treating a disorder related to an SS1 8-SSX fusion protein , SS1 8 wild-type protein, or SSX wild-type protein in a subject in need thereof, the method including administering to the subject an effective amount of an agent that reduces the level and/or activity of BRD9 in an SS1 8-SSX fusion protein-expressing cell in the subject. In some embodiments of any of the above aspects, the effective amount of the agent reduces the level and/or activity of BRD9 by at least 5% (e.g. , 6%, 7%, 8%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the agent that reduces the level and/or activity of BRD9 by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the agent that reduces the level and/or activity of BRD9 by at least 90% (e.g., 9 1% , 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%). In some embodiments, the effective amount of the agent reduces the level and/or activity of BRD9 by at least 5% (e.g. , 6%, 7%, 8%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least 12 hours (e.g., 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours, or more). In some embodiments, the effective amount of the agent that reduces the level and/or activity of BRD9 by at least 5% (e.g. , 6%, 7%, 8%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least 4 days (e.g. , 5 days, 6 days, 7 days, 14 days, 28 days, or more). In some embodiments, the subject has cancer. In some embodiments, the cancer expresses SS1 8-SSX fusion protein and/or the cell or subject has been identified as expressing SS1 8-SSX fusion protein. In some embodiments, the disorder is synovial sarcoma or Ewing’s sarcoma.
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