Discovery of potent, highly selective covalent irreversible BTK inhibitors from a fragment hit

[Display omitted] •A novel series of potent covalent irreversible BTK inhibitors was discovered from a fragment hit.•The optimization of the linker part was accomplished with the aid of MOE.•The top molecule showed comparable cellular potency to ibrutinib and higher kinome selectivity. Bruton's Tyrosine Kinase (BTK) is a member of the TEC kinase family that is expressed in cells of hematopoietic lineage (e.g., in B cells, macrophages, monocytes, and mast cells). Small molecule covalent irreversible BTK inhibitor targeting Cys481 within the ATP-binding pocket, for example ibrutinib, has been applied in the treatment of B-cell malignancies. Starting from a fragment hit, we discovered a novel series of potent covalent irreversible BTK inhibitors that occupy selectivity pocket of the active site of the BTK kinase domain. Guided by X-ray structures and a fragment-based drug design (FBDD) approach, we generated molecules showing comparable cellular potency to ibrutinib and higher kinome selectivity against undesirable off-targets like EGFR.