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
  • 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: [email protected].
  • 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: [email protected].
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.