2. Academic Validation
  3. 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

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

  • J Med Chem. 2017 Mar 9;60(5):1793-1816. doi: 10.1021/acs.jmedchem.6b01413.
Xiaofei Liang 1 2,  Fengchao Lv 1 3,  Beilei Wang 1 3,  Kailin Yu 1 3,  Hong Wu 1 2,  Ziping Qi 1 2,  Zongru Jiang 1 3,  Cheng Chen 1 3,  Aoli Wang 1 3,  Weili Miao 4,  Wenchao Wang 1 2,  Zhenquan Hu 1 2,  Juan Liu 1 3,  Xiaochuan Liu 1 2,  Zheng Zhao 1 2,  Li Wang 1 3,  Shanchuan Zhang 2 5,  Zi Ye 6,  Chu Wang 6,  Tao Ren 7,  Yinsheng Wang 4,  Qingsong Liu 1 2 3 7,  Jing Liu 1 2
Affiliations

Affiliations

  • 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.
PMID: 28140585 DOI: 10.1021/acs.jmedchem.6b01413
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.

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