2. Academic Validation
  3. Discovery of 2,5-diaminopyrimidine derivatives as the first series of selective monomeric degraders of B-lymphoid tyrosine kinase

Discovery of 2,5-diaminopyrimidine derivatives as the first series of selective monomeric degraders of B-lymphoid tyrosine kinase

  • Eur J Med Chem. 2023 Aug 5;256:115460. doi: 10.1016/j.ejmech.2023.115460.
Tiancheng Fu 1,  Yingying Zuo 1,  Gang Xue 1,  Danli Zhou 1,  Zhengying Pan 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, 518055, China.
  • 2 State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, 518055, China. Electronic address: panzy@pkusz.edu.cn.
PMID: 37163946 DOI: 10.1016/j.ejmech.2023.115460
Abstract

B-lymphoid tyrosine kinase (Blk) is an important knot of B cell receptor signaling, and regulates the function and development of B cells subset. Dysfunction of Blk is correlated with autoimmune diseases and Cancer. There is an urgent need to develop selective Blk modulators to facilitate the studies of Blk in biological processes. Herein, we report the discovery of a series of 2,5-diaminopyrimidine-based compounds capable of selectively degrading Blk. The optimized compounds 9-11 possess weak biochemical inhibitory activities against Blk, yet they effectively degrade Blk and show high selectivity for Blk over Other structurally and functionally related Src family and TEC family kinases. Furthermore, compounds 9 and 11 demonstrate potent inhibitory activities in several B-lymphoid cell lines. As the first series of effective and selective monomeric Blk degraders, compounds 9-11 serve as valuable tools for further investigation of the functions of Blk.

Keywords

B cell lymphoma; BLK; Monomeric degrader; Protein degradation.

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