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
  • 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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