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Bone marrow on x chromosome kinase (BMX) inhibitors and uses thereof

a chromosome kinase and inhibitor technology, applied in the field of bone marrow on x chromosome kinase inhibitors, can solve the problems of indirect downstream targets of bmx, substrate motifs of bmx and other tec kinases have not been identified, etc., to increase tyrosine kinase signaling, amplify tyrosine kinase signaling, and enhance downstream signaling

Inactive Publication Date: 2019-04-18
BETH ISRAEL DEACONESS MEDICAL CENT INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent is about a new discovery that a protein called BMX amplifies signals from certain molecules called tyrosine kinases. BMX is involved in a range of diseases that result from increased growth signals, including cancer, diabetes, and inflammatory diseases. The invention provides compounds that inhibit BMX, which could be used as medications to treat these diseases. The patent covers the methods for making and using BMX inhibitors.

Problems solved by technology

However, the direct downstream targets of BMX remain elusive, and substrate motifs for BMX and other Tec kinases have not been identified.

Method used

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  • Bone marrow on x chromosome kinase (BMX) inhibitors and uses thereof
  • Bone marrow on x chromosome kinase (BMX) inhibitors and uses thereof
  • Bone marrow on x chromosome kinase (BMX) inhibitors and uses thereof

Examples

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Effect test

example 1

on of the Compounds

[0366]Preparation of Compound 3

[0367]To a solution of 1 (540 mg, 2 mmol, 1 equiv.) in 1,4-dioxane (5 mL) at room temperature in a sealed tube was added 2 (354 mg, 2 mmol, 1 equiv.). The resultant mixture was heated to 80° C. for 4 h, cooled down to room temperature, quenched with NaOH (1N, 10 mL), and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL×3) and dried over Na2SO4. Volitiles were removed, and the residue was purified with silica gel flash chromatography (hexane:EtOAc=1:3) to give compound 3 (530 mg, 75% yield). LC-MS m / z (M+H): 385.10.

[0368]Preparation of Compound 4

[0369]To a solution of 3 (530 mg, 1.5 mmol, 1 equiv.) in EtOH (50 mL) at room temperature was added NaBH4 (285 mg, 5 equiv.). The resultant suspension was stirred at room temperature for 4 h and quenched with NaHCO3(saturated, 50 mL) carefully. Volitiles were removed, and the residue was diluted with water, extracted with CH2Cl2 (100 mL×2), and dried ov...

example 2

l Assays of the Compounds

[0380]Materials

[0381]Anti-pFAK (Y576 / 577), anti-pIGF-1R (Y1165 / 1166) / Insulin Receptor (Y1189 / 1190), anti-pMET (Y1234 / 1235), anti-pACK1 (Y857 / 858), anti-pFGFR1 (Y653 / 654), anti-pGSK(S9), anti-pS6 (S235 / 236), antipAKT(S473), anti-pAKT (T308), anti-ppl30Cas (Y410), anti-Myc tag, anti-MET and anti-IR were obtained from Cell Signaling Technology (Danvers, Mass.). Anti-Flag M2, anti-FAK, anti-pFAK (pY576), anti-pFAK (pY577), anti-PHLPP were obtained from Abcam (Cambridge, Mass.). Anti-BMX and anti-j3-actin were obtained from Santa Cruz Biotechnology (Santa Cruz, Calif.). Anti-pTyr (4G10) and anti-tubulin were obtained from Millipore (Billerica, Mass.). Bmxtides were obtained from GenScript Corporation (Piscataway, N.J.). BMX and control siRNA were obtained from Dharmacon (Lafayette, Colo.). 3×Flag-FAK was produced by inserting FAK (pCMV-SPORT6-FAK, Open Biosystems (Lafayette, Colo.)) into p3×Flag-CMV (Sigma-Aldrich, St. Louis, Mo.) between HindIII and BamH1 sites,...

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Abstract

The present invention provides novel compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods and kits involving the compounds of Formula (I) or (II), or compositions thereof, for treating or preventing a wide range of diseases (e.g., proliferative diseases (e.g., cancers, benign neoplasms, angiogenesis, inflammatory diseases, autoimmune diseases) and metabolic diseases (e.g., diabetes (e.g., type 2 diabetes, gestational diabetes)) in a subject. Treatment of a subject with a disease using a compound of Formula (I) or (II), or compositions thereof, may downregulate the expression and / or inhibit the activity of a kinase (e.g., a tyrosine kinase, such as a Tec kinase, in particular, bone marrow on X chromosome kinase (BMX)), and therefore, suppress tyrosine kinase singling in the subject.

Description

RELATED APPLICATIONS[0001]This application is a continuation of and claims priority under 35 U.S.C. § 120 to U.S. patent application U.S. Ser. No. 14 / 436,387, filed Apr. 16, 2015, which is a national stage filing under 35 U.S.C. § 371 of international PCT application, PCT / US2013 / 065689, filed Oct. 18, 2013, which claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Applications, U.S. Ser. No. 61 / 716,273, filed Oct. 19, 2012, and U.S. Ser. No. 61 / 717,345, filed Oct. 23, 2012, each of which is incorporated herein by reference.GOVERNMENT SUPPORT[0002]This invention was made with government support under grant number W81XWH-09-1-0435 awarded by the U.S. Department of the Army. The government has certain rights in the invention.BACKGROUND OF THE INVENTION[0003]“Bone Marrow on X chromosome” kinase (BMX, also termed ETK) is a non-receptor tyrosine kinase and is activated downstream of phosphatidylinositol-3 kinase (PI-3K) and v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D471/04
CPCC07D471/04A61P35/00
Inventor GRAY, NATHANAELBALK, STEVENLIU, QINGSONGCHEN, SEN
Owner BETH ISRAEL DEACONESS MEDICAL CENT INC
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