Vecabrutinib

Vecabrutinib (SNS-062) is a potent, noncovalent BTK and ITK inhibitor, with K_d values of 0.3 nM and 2.2 nM, respectively. Vecabrutinib shows an IC₅₀ of 24 nM for ITK^[1][2]. IC50 & Target: IC50: 24 nM (ITK)^[2]
Kd: 0.3 nM (BTK), 2.2 nM (ITK)^[1] In Vitro: Vecabrutinib inhibits pBTK in human whole blood with an average IC₅₀ of 50 nM. Vecabrutinib inhibits WT and C481S BTK with similar IC₅₀s (pBTK IC₅₀s: WT BTK 2.9 nM, C481S BTK 4.4 nM)^[1]. 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 is six times more potent than PCI-32765 and greater than 640 times more potent than acalabrutinib against C481S BTK. Vecabrutinib demonstrates dose-dependent inhibition of BTK in primary patient CLL cells comparable to PCI-32765 via immunoblot for BTK phosphorylation. Vecabrutinib decreases viability of primary CLL cells in the presence of HS5 stromal protection by 5.5%^[2]. In Vivo: Vecabrutinib has good oral bioavailability in rat and dog (%F ≥ 40%) and a terminal half-life of 5 to 6 hours. Vecabrutinib is well tolerated with continuous drug levels and at exposures much greater than those achieved for PCI-32765^[1].