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

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.