p38α belongs to the family of mitogen-activated protein kinases. VX-745 is a potent p38α inhibitor with an IC50 value of 9 nM and it shows 20-fold selectivity for p38α over p38β. In human peripheral blood mononuclear cells, VX-745 blocks IL-1β and TNFα with IC50 values of 45 and 51 nM, respectively. It also effectively inhibited IL-1β and TNFα in whole blood with IC50 values of 150 and 180 nM, respectively. However, the IC50 values for the inhibition against CYPs 3A4, 2D6, 2C19, 2C9, and 1A2 were above 40 μM[1]. VX-745 (0.06 – 20 μM, 48h incubation) significantly reduced the release of IL-6 in the bone marrow stromal cells (BMSCs) from patients with multiple myeloma, and the peak inhibitory effect was observed when 2 μM VX-745 was used. VX-745 at 0.05, 0.5, and 5 μM inhibited TNF-α–induced increase of IL-6 in BMSCs. The cell growth of MM.1S, RPMI8226, and U266 cell lines were inhibited by VX-745 with an IC50 value of 10 μM[2]. In murine collagen-induced arthritis model, 20-day treatment of VX-745 at 2.5, 5, and 10 mg/kg (twice daily) showed 27%, 31%, and 44% improvement in the inflammatory scores, respectively, compared to control mice. It was also found that VX-745 treatment protected 32 – 39% bone and cartilage erosion[1].
作用机制
VX-745 is a selective p38α inhibitor. The 2,4-difluorophenyl ring of VX-745 occupies a hydrophobic pocket at T106 residue to make extensive van der Waals contacts with p38α. p38α also facilitates the binding of VX-745 by flipping the G110 backbone[1].
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