Overcoming Resistance: The Efficacy of SNS-062 in Targeting Both Wild-Type and Mutant BTK in B-Cell Malignancies

SNS-062 is a novel, potent noncovalent inhibitor of Bruton's tyrosine kinase (BTK) that also targets ITK, offering a potential new treatment for B-cell malignancies. This compound has been developed as an alternative for patients who may have developed or acquired resistance to the BTK inhibitor ibrutinib, often due to mutations in the BTK active site cysteine (C481).

In vitro assays showed that SNS-062 selectively binds to a subset of kinases, including BTK and ITK, without affecting EGFR. This selective binding could potentially result in fewer off-target side effects compared to ibrutinib, which is linked to gastrointestinal and skin reactions due to its impact on EGFR.

SNS-062 effectively inhibits BTK autophosphorylation in human blood with an average IC50 of 50 nM and demonstrates a pharmacokinetic/pharmacodynamic relationship in mice, with an in vivo IC50 for pBTK inhibition of 47 nM. The compound showed efficacy in a mouse model of B cell-mediated antibody response and in a rat model of collagen-induced arthritis.

Notably, SNS-062 maintained its inhibitory activity against both wild type and the C481S mutant BTK, whereas ibrutinib's potency was significantly reduced against the mutant. SNS-062 also exhibited good oral bioavailability in preclinical species and a terminal half-life suitable for sustained inhibition of BTK.

In 28-day toxicology studies, SNS-062 was well-tolerated with drug levels and exposures much higher than those required for ibrutinib, suggesting that effective plasma concentrations of SNS-062 could be achieved for prolonged BTK inhibition.

The collective data suggest that SNS-062 has a favorable pharmacokinetic and safety profile, supporting its clinical development for the treatment of B-cell malignancies, especially for patients with chronic lymphocytic leukemia (CLL) who have developed resistance to ibrutinib.