Targeting Ibrutinib Resistant BTK C481S Mutation with ARQ 531, a Reversible Non Covalent Inhibitor of BTK
The B cell receptor (BCR) signaling pathway is a central determinant of B cell fate and function and Bruton tyrosine kinase (BTK) is a critical component of this signaling cascade. BTK, a nonreceptor tyrosine kinase, plays a significant role in B cell development and is a unique therapeutic target in B cell malignancies. Targeting BTK with the irreversible, inhibitor ibrutinib achieved an impressive objective response rate in patients with CLL. However, disease progression occurs more frequently in these patients with high risk genomic features either shortly after the start of ibrutinib therapy or later with progressive CLL. Disease progression is often associated with resistance to ibrutinib with acquired BTK mutation on C481 residue which prevent covalent binding of ibrutinib to BTK. Here we present discovery and preclinical development of potent reversible BTK inhibitor, ARQ 531, capable of inhibiting activation of both wild type and the C481S mutant of BTK and subsequent downstream oncogenic signaling in various hematological malignancies.