LOXO-305 is a novel, selective and reversible Bruton's tyrosine kinase (BTK) inhibitor with equivalent potency against wild-type and cysteine-481 (C481) mutated BTK.

We believe that the widespread use of covalent BTK inhibitors, such as ibrutinib, will increasingly drive acquired resistance through a mutational event in BTK called C481S, leading to a group of relapsing patients in need of new therapies. Our work suggests that a highly selective, reversible BTK inhibitor can address this emerging unmet need in patients whose disease has progressed on a covalent BTK inhibitor.  

LOXO-305 was designed to reversibly bind BTK and preserve activity in the presence of the C481S acquired resistance mutation. Additionally, it was designed to avoid off-target kinases that have complicated the development of both covalent and reversible BTK inhibitors, such as EGFR, ITK, BMX, TEC, ITK, BLK, LCK, and SRC.