2. Academic Validation
  3. Discovery of N-(3-(5-((3-acrylamido-4-(morpholine-4-carbonyl)phenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl)-4-(tert-butyl)benzamide (CHMFL-BTK-01) as a highly selective irreversible Bruton's tyrosine kinase (BTK) inhibitor

Discovery of N-(3-(5-((3-acrylamido-4-(morpholine-4-carbonyl)phenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl)-4-(tert-butyl)benzamide (CHMFL-BTK-01) as a highly selective irreversible Bruton's tyrosine kinase (BTK) inhibitor

  • Eur J Med Chem. 2017 May 5;131:107-125. doi: 10.1016/j.ejmech.2017.03.001.
Qianmao Liang 1,  Yongfei Chen 2,  Kailin Yu 3,  Cheng Chen 2,  Shouxiang Zhang 4,  Aoli Wang 3,  Wei Wang 2,  Hong Wu 3,  Xiaochuan Liu 1,  Beilei Wang 2,  Li Wang 2,  Zhenquan Hu 2,  Wenchao Wang 2,  Tao Ren 5,  Shanchun Zhang 6,  Qingsong Liu 7,  Cai-Hong Yun 8,  Jing Liu 9
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230036, PR China; High Magnetic Field Laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, PR China.
  • 2 High Magnetic Field Laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, PR China; CHMFL-HCMTC Target Therapy Joint Laboratory, 350 Shushanhu Road, Hefei, Anhui 230031, PR China.
  • 3 High Magnetic Field Laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, PR China; University of Science and Technology of China, Hefei, Anhui 230036, PR China.
  • 4 Institute of Systems Biomedicine, Department of Biophysics, Beijing Key Laboratory of Tumor Systems Biology and Center for Molecular and Translational Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, PR China.
  • 5 Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230088, PR China.
  • 6 CHMFL-HCMTC Target Therapy Joint Laboratory, 350 Shushanhu Road, Hefei, Anhui 230031, PR China; Hefei Cosource Medicine Technology Co. LTD., 358 Ganquan Road, Hefei, Anhui 230031, PR China.
  • 7 High Magnetic Field Laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, PR China; CHMFL-HCMTC Target Therapy Joint Laboratory, 350 Shushanhu Road, Hefei, Anhui 230031, PR China; University of Science and Technology of China, Hefei, Anhui 230036, PR China; Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230088, PR China.
  • 8 Institute of Systems Biomedicine, Department of Biophysics, Beijing Key Laboratory of Tumor Systems Biology and Center for Molecular and Translational Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, PR China. Electronic address: yunch@hsc.pku.edu.cn.
  • 9 High Magnetic Field Laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, PR China; CHMFL-HCMTC Target Therapy Joint Laboratory, 350 Shushanhu Road, Hefei, Anhui 230031, PR China. Electronic address: jingliu@hmfl.ac.cn.
PMID: 28315597 DOI: 10.1016/j.ejmech.2017.03.001
Abstract

Currently there are several irreversible Btk inhibitors targeting Cys481 residue under preclinical or clinical development. However, most of these inhibitors also targeted other kinases such as BMX, JAK3, and EGFR that bear the highly similar active cysteine residues. Through a structure-based drug design approach, we discovered a highly potent (IC50: 7 nM) irreversible Btk Inhibitor compound 9 (CHMFL-BTK-01), which displayed a high selectivity profile in KINOMEscan (S score (35) = 0.00) among 468 kinases/mutants at the concentration of 1 μM. Compound 9 completely abolished BMX, JAK3 and EGFR's activity. Both X-ray crystal structure and cysteine-serine mutation mediated rescue experiment confirmed 9's irreversible binding mode. 9 also potently inhibited Btk Y223 auto-phosphorylation (EC50: <30 nM), arrested cell cycle in G0/G1 phase and induced Apoptosis in U2932 and Pfeiffer cells. We believe these features would make 9 a good pharmacological tool to study the Btk related pathology.

Keywords

B-cell lymphoma; BTK; Irreversible inhibitor; Kinase inhibitor; Structure-activity relationship.

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