2. Academic Validation
  3. Structure-activity relationship investigation for benzonaphthyridinone derivatives as novel potent Bruton's tyrosine kinase (BTK) irreversible inhibitors

Structure-activity relationship investigation for benzonaphthyridinone derivatives as novel potent Bruton's tyrosine kinase (BTK) irreversible inhibitors

  • Eur J Med Chem. 2017 Sep 8:137:545-557. doi: 10.1016/j.ejmech.2017.06.016.
Beilei Wang 1,  Yuanxin Deng 1,  Yongfei Chen 2,  Kailin Yu 1,  Aoli Wang 1,  Qianmao Liang 3,  Wei Wang 2,  Cheng Chen 1,  Hong Wu 2,  Chen Hu 1,  Weili Miao 4,  Wooyoung Hur 5,  Wenchao Wang 1,  Zhenquan Hu 2,  Ellen L Weisberg 5,  Jinhua Wang 6,  Tao Ren 7,  Yinsheng Wang 4,  Nathanael S Gray 6,  Qingsong Liu 8,  Jing Liu 9
Affiliations

Affiliations

  • 1 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.
  • 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.
  • 4 Department of Chemistry, University of California-Riverside, 900 University Ave., Riverside, CA 92521, USA.
  • 5 Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave., Boston, MA 02115, USA.
  • 6 Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 250 Longwood Ave, SGM 628, Boston, MA 02115, USA.
  • 7 Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230088, PR China.
  • 8 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; CHMFL-HCMTC Target Therapy Joint Laboratory, 350 Shushanhu Road, Hefei Anhui 230031, 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; Hefei Science Center, Chinese Academy of Sciences, 350 Shushanhu Road, Hefei, Anhui, 230031, PR China. Electronic address: qsliu97@hmfl.ac.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: 28628824 DOI: 10.1016/j.ejmech.2017.06.016
Abstract

Through a structure-based drug design approach, a tricyclic benzonaphthyridinone pharmacophore was used as a starting point for carrying out detailed medicinal structure-activity relationhip (SAR) studies geared toward characterization of a panel of proposed Btk inhibitors, including 6 (QL-X-138), 7 (BMX-IN-1) and 8 (QL47). These studies led to the discovery of the novel potent irreversible Btk Inhibitor, compound 18 (CHMFL-BTK-11). Kinetic analysis of compound 18 revealed an irreversible binding efficacy (kinact/Ki) of 0.01 μM-1s-1. Compound 18 potently inhibited Btk kinase Y223 auto-phosphorylation (EC50 < 100 nM), arrested cell cycle in G0/G1 phase, and induced Apoptosis in Ramos, MOLM13 and Pfeiffer cells. We believe these features would make 18 a good pharmacological tool for studying BTK-related pathologies.

Keywords

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

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