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

Beilei Wang; Yuanxin Deng; Yongfei Chen; Kailin Yu; Aoli Wang; Qianmao Liang; Wei Wang; Cheng Chen; Hong Wu; Chen Hu; Weili Miao; Wooyoung Hur; Wenchao Wang; Zhenquan Hu; Ellen L Weisberg; Jinhua Wang; Tao Ren; Yinsheng Wang; Nathanael S Gray; Qingsong Liu; Jing Liu

doi:10.1016/j.ejmech.2017.06.016

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. Epub 2017 Jun 9.

Authors

Beilei Wang¹, Yuanxin Deng¹, Yongfei Chen², Kailin Yu¹, Aoli Wang¹, Qianmao Liang³, Wei Wang², Cheng Chen¹, Hong Wu², Chen Hu¹, Weili Miao⁴, Wooyoung Hur⁵, Wenchao Wang¹, Zhenquan Hu², Ellen L Weisberg⁵, Jinhua Wang⁶, Tao Ren⁷, Yinsheng Wang⁴, Nathanael S Gray⁶, Qingsong Liu⁸, Jing Liu⁹

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 (k_inact/K_i) 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.

MeSH terms

Agammaglobulinaemia Tyrosine Kinase
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Cycle Checkpoints / drug effects
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Kinetics
Models, Molecular
Molecular Structure
Naphthyridines / chemical synthesis
Naphthyridines / chemistry
Naphthyridines / pharmacology*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / metabolism
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Naphthyridines
Protein Kinase Inhibitors
Protein-Tyrosine Kinases
Agammaglobulinaemia Tyrosine Kinase
BTK protein, human