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J Med Chem. 2017 Mar 9;60(5):1793-1816. doi: 10.1021/acs.jmedchem.6b01413. Epub 2017 Feb 14.

Discovery of 2-((3-Acrylamido-4-methylphenyl)amino)-N-(2-methyl-5-(3,4,5-trimethoxybenzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-BMX-078) as a Highly Potent and Selective Type II Irreversible Bone Marrow Kinase in the X Chromosome (BMX) Kinase Inhibitor.

Liang X1,2, Lv F1,3, Wang B1,3, Yu K1,3, Wu H1,2, Qi Z1,2, Jiang Z1,3, Chen C1,3, Wang A1,3, Miao W4, Wang W1,2, Hu Z1,2, Liu J1,3, Liu X1,2, Zhao Z1,2, Wang L1,3, Zhang S2,5, Ye Z6, Wang C6, Ren T7, Wang Y4, Liu Q1,2,3,7, Liu J1,2.

Author information

1
High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.
2
CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.
3
University of Science and Technology of China , Hefei, Anhui 230036, P. R. China.
4
Department of Chemistry, University of California-Riverside , 900 University Avenue, Riverside, California 92521, United States.
5
Hefei Cosource Medicine Technology Co. Ltd. , 358 Ganquan Road, Hefei, Anhui 230031, P. R. China.
6
Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking-Tsinghua Center for Life Sciences, Peking University , Beijing 100871, P. R. China.
7
Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences , Hefei, Anhui 230088, P. R. China.

Abstract

BMX is a member of TEC family nonreceptor tyrosine kinase and is involved in a variety of critical physiological and pathological processes. Through combination of irreversible inhibitor design and type II inhibitor design approaches, we have discovered a highly selective and potent type II irreversible BMX kinase inhibitor compound 41 (CHMFL-BMX-078), which exhibited an IC50 of 11 nM by formation of a covalent bond with cysteine 496 residue in the DFG-out inactive conformation of BMX. It displayed a high selectivity profile (S score(1) = 0.01) against the 468 kinases/mutants in the KINOMEscan evaluation and achieved at least 40-fold selectivity over BTK kinase. Given the fact that BMX mediated signaling pathway is still not fully understood, compound 41 would serve as a useful pharmacological tool to elucidate the detailed mechanism of BMX mediated signaling pathways.

PMID:
28140585
DOI:
10.1021/acs.jmedchem.6b01413
[Indexed for MEDLINE]

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