AZ628 is a potent and newly discorvered inhibitor of BRAF, c-Raf-1 and BRAFV600E with IC50 values of 105 nM, 29 nM and 34 nM, respectively. This compound prevents CRAF activation through persistently occupying the ATP-binding site of Raf kinase. Specificity profile suggests that AZ628 also inhibits activation of other tyrosine protein kinases such as DDR2, VEGFR2, Lyn, Flt1, FMS and others.
Raf kinases a family of three serine/threonine-specific protein kinases and participate in the RAS-RAF-MEK-ERK signal transduction cascade, also known as the mitogen-activated protein kinase (MAPK) cascade. The activation of MAPK signaling leads to different cellular response such as cell proliferation, apoptosis and inflammation.
AZ628 has the potent anti-tumor activity. In human colon and melanoma-derived cell line that carries the recurrent V600E activating BRAF mutation, AZ628 was shown to inhibit anchorage-dependent and -independent growth, induce cell cycle arrest, and cause apoptosis [1]. AZ628 may be antiangiogenic due to inhibition of VEGFR2 [2].
Generation of melanoma cell line clones is obtained resistance to the RAF kinase inhibitor AZ628. Resistance to AZ628 is connected with raised levels of the RAF downstream effector p-ERK1/2. ERK1/2 initiation in AZ628-resistant clones is interceded by MEK. Supported multiplication of AZ628-resistant clones is to a great extent autonomous of BRAF kinase action. AZ628-resistant clones express elevated CRAF. Survival of AZ628-safe cells is subject to CRAF [1].
References:
1. Montagut C, Sharma SV, Shioda T, McDermott U, Ulman M, Ulkus LE, et al. Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res 2008,68:4853-4861.
2. Khazak V, Astsaturov I, Serebriiskii IG, Golemis EA. Selective Raf inhibition in cancer therapy. Expert Opin Ther Targets 2007,11:1587-1609.