Abstract C186: SNS-062 is a potent noncovalent BTK inhibitor with comparable activity against wild type BTK and BTK with an acquired resistance mutation

Background and purpose: BTK mediates B-cell receptor signaling and was validated as a target by the BTK inhibitor ibrutinib in several B-cell malignancies, including mantle cell lymphoma and chronic lymphocytic leukemia (CLL). However, patients may have or acquire resistance. Resistance mechanisms include mutation of the cysteine in the BTK active site that ibrutinib requires for covalent binding (C481). We identified and characterized SNS-062, a potent, noncovalent BTK inhibitor with activity towards BTK harboring resistance mutations that also inhibits ITK and may provide enhanced anti-tumor immune responses. SNS-062 shows restricted kinase selectivity and nonclinical pharmacology, pharmacokinetics (PK) and toxicology profiles distinct from ibrutinib and merits clinical investigation. Methods and Results: In in vitro kinase binding assays, SNS-062 bound to 9 kinases with Kd Citation Format: Minke E. Binnerts, Kevin L. Otipoby, Brian T. Hopkins, Tonika Bohnert, Stig Hansen, Gene Jamieson, Pamela A. Howland, Eric H. Bjerkholt, Deborah A. Thomas, Judith A. Fox, Adam R. Craig. SNS-062 is a potent noncovalent BTK inhibitor with comparable activity against wild type BTK and BTK with an acquired resistance mutation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C186.