Discovery of Reversible, Noncovalent Bruton's Tyrosine Kinase Inhibitors Targeting BTK C481S Mutation.

Bruton's tyrosine kinase (BTK) is a promising target for treatment of B-cell malignancies and autoimmune disorders. Application of first- and second-generation irreversible BTK inhibitors against various lymphomas and leukemia is well-known. Some clinical limitations, such as off-target toxicity and primary or acquired drug resistance mutations including BTK C481S have been observed for irreversible BTK inhibitors. Developing selective reversible, noncovalent BTK inhibitors is a suitable strategy to overcome drug resistance problems. Recent approval of pirtobrutinib by the FDA in 2023 stimulated research interests for developing noncovalent mutant selective BTK inhibitors. In this letter, we report the discovery of a novel series of 1-pyrrolo-[2,3-]-pyridine derivatives as novel, selective next-generation BTK inhibitors targeting the BTK C481S mutation. One of the best compounds of the series, compound showed efficacy and induced tumor suppression (TGI up to 82%) in mutant BTK mouse xenograft models.