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  3. Discovery of new non-covalent reversible BTK inhibitors: Synthesis, in silico studies, and in vitro evaluations

Discovery of new non-covalent reversible BTK inhibitors: Synthesis, in silico studies, and in vitro evaluations

  • Chem Biol Interact. 2024 Nov 1:403:111241. doi: 10.1016/j.cbi.2024.111241.
Zunyuan Wang 1,  Shu Wang 2,  Youkun Kang 2,  Xinglong Chi 2,  Youlu Pan 3,  Shenxin Zeng 3,  Chixiao Zhang 3,  Xiangwei Xu 4,  Wenyong Wang 5,  Wenhai Huang 6
Affiliations

Affiliations

  • 1 Affiliated Yongkang First People's Hospital and School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 310013, China; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, 310013, China; Key Discipline of Zhejiang Province in Public Health and Preventive Medicine (First Class, Category A), Hangzhou Medical College, Hangzhou, 310013, China.
  • 2 Affiliated Yongkang First People's Hospital and School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 310013, China.
  • 3 Affiliated Yongkang First People's Hospital and School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 310013, China; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, 310013, China.
  • 4 Affiliated Yongkang First People's Hospital and School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 310013, China; Yongkang First People's Hospital, Yongkang, 321306, China.
  • 5 Affiliated Yongkang First People's Hospital and School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 310013, China; Yongkang First People's Hospital, Yongkang, 321306, China. Electronic address: 956991592@qq.com.
  • 6 Affiliated Yongkang First People's Hospital and School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 310013, China; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, 310013, China; Key Discipline of Zhejiang Province in Public Health and Preventive Medicine (First Class, Category A), Hangzhou Medical College, Hangzhou, 310013, China. Electronic address: hwh@hmc.edu.cn.
PMID: 39278457 DOI: 10.1016/j.cbi.2024.111241
Abstract

Bruton's Tyrosine Kinase (Btk) played a key role in the B cell antigen receptor (BCR) signaling pathway, and was considered a hotspot in the treatment of B cell malignant tumors and B cell immune diseases. There were 5 covalent irreversible inhibitors launched currently on the market, but C481S mutation was detected in most patients after administration. The approval of Pirtobrutinib (Jaypirca) by FDA in 2023 aroused great interest in the development of non-covalent and reversible Btk inhibitors. In order to solve the resistance of covalent irreversible inhibitors caused by C481S mutation, 11 reversible Btk inhibitors were designed based on screening in this article. The design, synthesis, in silico studies, and in vitro evaluations were performed for further verification. Among them, compound WS-11 showed best activity with IC50 of 3.9 nM for wild type, 2.2 nM for C481S mutation Btk, which was comparable to the positive control Pirtobrutinib. Furthermore, WS-11 would have a good druglikeness properties predicted by pkCSM and SwissADME, which provided a promising lead for further optimization and development.

Keywords

BTK; Design; Reversible inhibitor; Synthesis.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-169228
    BTK Inhibitor
    Btk