WO 2015/185998 A2 10 December 2015 (10.12.2015) P O P C T
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(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 2015/185998 A2 10 December 2015 (10.12.2015) P O P C T (51) International Patent Classification: Not classified (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (21) Number: International Application AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, PCT/IB20 15/00 1425 BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (22) International Filing Date: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 10 April 2015 (10.04.2015) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (25) Filing Language: English MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (26) Publication Language: English PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (30) Priority Data: TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 61/978,760 11 April 2014 ( 11.04.2014) US (84) Designated States (unless otherwise indicated, for every (71) Applicant: ACERTA PHARMA B.V. [NL/NL]; Pivot kind of regional protection available): ARIPO (BW, GH, Park Room Rk 2 111, NL-5349 AC OSS Molenweg 79 GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (NL). TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (72) Inventors: IZUMI, Raquel; 3437 Brittan Avenue, San DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Carlos, CA 94070 (US). SALVA, Francisco; 188 South LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Park Street, # 12, San Francisco, CA 94107 (US). HAM- SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, DY, Ahmed; 640 Henry Cowell Drive, Santa Cruz, CA GW, KM, ML, MR, NE, SN, TD, TG). 95060 (US). Published: (74) Agent: SECERNA LLP; The Catalyst, Baird Lane, Hes- lington East, York YO10 5GA (GB). — without international search report and to be republished upon receipt of that report (Rule 48.2(g)) (54) Title: METHODS OF BLOCKING THE CXCR-4/SDF-1 SIGNALING PATHWAY WITH INHIBITORS OF BONE MAR ROW X KINASE (57) Abstract: In some embodiments, the present invention relates to novel small molecule inhibitors that block the CX- CR4-SDF-1 signaling pathway by directly inhibiting mem bers of the Tec family of kinases, namely bone marrow X kinase (BMX) (also known as epithelial and endothelial tyr osine kinase (ETK)), and their use in treating diseases in which pathogenesis is mediated by the CXCR4/SDF-1 signal ing pathway. < oo 00 METHODS OF BLOCKING THE CXCR-4/SDF-1 SIGNALING PATHWAY WITH INHIBITORS OF BONE MARROW X KINASE FIELD OF THE INVENTION [001] In some embodiments, the present invention relates to novel small molecule inhibitors that block the CXCR4-SDF-1 signaling pathway by directly inhibiting members of the Tec family of kinases, namely bone marrow X kinase (BMX) (also known as bone marrow tyrosine kinase gene in chromasone X and epithelial and endothelial tyrosine kinase (ETK)), and their use in treating diseases in which pathogenesis is mediated by the CXCR4/SDF-1 signaling pathway. BACKGROUND OF THE INVENTION [002] CXCR4, a G-protein-coupled receptor, and its naturally occurring ligand, stromal cell- derived factor- 1 (SDF-1; CXCL12), are a chemokine receptor- ligand pair. CXCR4 is constitutive ly or over-expressed in a wide variety of human cancers (Table 1). SDF-1, the only known ligand of CXCR4, is highly expressed in tumor microenvironments, as well as in bone marrow, lung, liver, and lymph nodes, i.e., organ sites most commonly involved in tumor metastasis. CXCR4/SDF-1 interaction plays important roles in multiple stages of tumorigenesis, including tumor growth, invasion, angiogenesis, and metastasis (Furusato, et a , Pathology International 2010, 60, 497-505). The CXCR4/SDF1 axis also serves a role in attraction multiple leukocyte subsets and stimulation B cell production and myelopoeisis, all of which are implicated in autoimmune diseases (Chong and Mohan, Expert Opin. Ther. Targets 2009, 13(10), 1147-1 153). In view of the involvement of CXCR4/SDF-1 in these serious diseases, the CXCR4/SDF-1 pathway may be an attractive therapeutic target (Tamamura and Fujii, Expert Opin. Ther. Targets 2005, 9(6), 1267-1282). TABLE 1. CXCR4+ Expressing Tumors. Leukemias Brian tumors Small cell lung cancer Breast cancer Prostate cancer Rhabdomyosarcoma Neuroblastoma Wilms' tumor Hepatoblastoma Ovarian cancer Cervical cancer Osteosarcoma Sources: Kucia, et al., Stem Cells 2005, 23, 879-894; Furusato, et al. 2010, 60, 497-505; Retz, et al., Int. J. Cancer 2005, 114, 182- 189. [003] Tec kinases represent the second largest family of nonreceptor tyrosine kinases and are activated in response to cellular stimulation by antigen receptors, integrins, growth factors, cytokines and G protein-coupled receptors (Qiu and Kung, Oncogene 2000, 19, 5651-5661). The mammalian Tec family consists of five members: Tec, BTK, Itk/Emt/Tsk, Rlk/Txk, and BMX/ETK (Mano, Cytokine Growth Factor Rev., 1999, 10, 267-280). With some exceptions, Tec kinases are expressed primarily in cells of hematopoietic lineages. [004] BMX (also known as epithelial and endothelial tyrosine kinase (ETK)) is a Tec family kinase member expressed in granulocytes, monocytes, and is the only Tec family member expressed in cells of epithelial and endothelial lineages. Interestingly, it is also up regulated in various cancers including bladder cancer (Guo, et al, PLoS ONE 2011, 6(3), el7778) and prostate cancer (Dai, et al., Cancer Res. 2010, 70, 5587-5596). BMX contains an NH2-terminal Pleckstrin homology domain, a Src homology 3 domain, a Src homology 2 domain, and a COOH-terminal tyrosine kinase domain. Unlike other Tec-family kinases that are preferentially expressed in hematopoietic cells, BMX is expressed in other cell types as well, including endothelial, epithelial, and importantly metastatic carcinoma cells (Qiu, et al. , Proc. Natl. Acad. Sci. USA, 1998, 95, 3644-3649). BMX is activated by Gaq, Gal2 and Gal3. Thus, BMX plays an important role in G protein signaling and makes an attractive target for inhibition of CXCR4 signaling. SUMMARY OF THE INVENTION [005] Disclosed herein is the discovery that some BMX inhibitors surprisingly block the CXCR4/SDF-1 signaling pathway. Accordingly, provided herein are methods of blocking the CXCR4/SDF-1 signaling in a subject in need thereof comprising administering to the subject a BMX inhibitor in an amount effective to block said CXCR4/SDF-1 signaling pathway. These methods may be used in the treatment of disorders associated with overexpression of CXCR4 or dysregulation of CXCR4 signaling, e.g., autoimmune disorders or hematologic or nonhematologic malignancies. [006] In an embodiment, the invention provides a BMX inhibitor capable of blocking the CXCR4/SDF-1 signaling pathway. [007] In another aspect, the present invention provides a pharmaceutical composition, comprising a BMX inhibitor or pharmaceutically acceptable salt thereof as variously described above, and a pharmaceutically acceptable carrier, diluent, or excipient. [008] In another aspect, the present invention provides a BMX inhibitor or pharmaceutically acceptable salt thereof as variously described above, for use in therapy. [009] In another aspect, the present invention provides a BMX inhibitor or pharmaceutically acceptable salt thereof as variously described above, for the treatment of autoimmune disorders or hematologic or nonhematologic malignancies. [0010] In another aspect, the present invention provides the use of a BMX inhibitor or pharmaceutically acceptable salt thereof as variously described above, for the manufacture of a medicament for the treatment of autoimmune disorders or hematologic or nonhematologic malignancies. [0011] In another aspect, the present invention provides a method of treating autoimmune disorders or hematologic or nonhematologic malignancies comprising administering to a patient in need thereof an effective amount of a BMX inhibitor or pharmaceutically acceptable salt thereof as variously described above. BRIEF DESCRIPTION OF THE DRAWINGS [0012] The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings. [0013] FIG. 1 illustrates CD20+ B cell fluorescence, showing that CXCR-4/SDF-1 signalling is inhibited by the BMX inhibitor of Formula (II). [0014] FIG. 2 illustrates CD14+ monocyte cell fluorescence, showing that CXCR-4/SDF-1 signalling is inhibited by the BMX inhibitor of Formula (II). [0015] FIG. 3 illustrates CXCR4 surface expression in B-CLL (B cell chronic lymphocytic leukemia) following administration of the BMX inhibitor of Formula (II). [0016] FIG. 4 illustrates CXCR4 surface expression in B-CLL following administration of the BMX inhibitor of Formula (II). [0017] FIG. 5 illustrates that BMX inhibition is not impacting the ability of CD34+ cells to migrate towards SDF-1 (CXCL-12) in fresh CD34+ cells. [0018] FIG. 6 illustrates that BMX inhibition is not impacting the ability of CD34+ cells to migrate towards SDF-1 (CXCL-12) in cryopreserved CD34+ cells. [0019] FIG. 7 illustrates that BMX inhibition is not impacting the ability of U937 cells to migrate towards SDF-1 (CXCL-12). [0020] FIG. 8 illustrates that BMX inhibition is not impacting the ability of CLL cells to migrate towards SDF-1 (CXCL-12). [0021] FIG. 9 illustrates the results of a RANK MDA-MB23 1 mouse experiment. DETAILED DESCRIPTION OF THE INVENTION [0022] While preferred embodiments of the invention are shown and described herein, such embodiments are provided by way of example only and are not intended to otherwise limit the scope of the invention.