Vecabrutinib (SNS-062) is a potent and noncovalent BTK and ITK inhibitor (Kd: 0.3 nM and 2.2 nM, respectively). Vecabrutinib displays an IC50 of 24 nM for ITK.

Vecabrutinib is six times more potent than PCI-32765 and greater than 640 times more potent than acalabrutinib against C481S BTK. Vecabrutinib inhibits pBTK in human whole blood (average IC50: 50 nM). Vecabrutinib inhibits WT and C481S BTK with similar IC50s (pBTK IC50s: 2.9 nM and 4.4 nM for WT BTK and C481S BTK). In a recombinant kinase assay, IC50s of Vecabrutinib against WT BTK and C481S BTK are 4.6 nM and 1.1 nM. Vecabrutinib retains activity against the mutated BTK variant. Vecabrutinib demonstrates dose-dependent inhibition of BTK in primary patient CLL cells comparable to PCI-32765 via immunoblot for BTK phosphorylation. Vecabrutinib decreases the viability of primary CLL cells in the presence of HS5 stromal protection by 5.5% [1][2].

Vecabrutinib is well tolerated with continuous drug levels. Vecabrutinib has good oral bioavailability in rat and dog (%F ≥ 40%) and a terminal half-life of 5 to 6 hours [1].