AMG 47a

AMG 47a is an orally bioavailable inhibitor of Lck, VEGF receptor 2 (VEGFR2/KDR), p38α, and JAK3 (IC₅₀s = 0.2, 1, 3, and 72 nM, respectively).¹ It is selective for these kinases over a panel of additional kinases including SYK, JNK1, and PKAβ (IC₅₀s = 292 to >25,000 nM) but does inhibit Src (IC₅₀ = 2 nM). It decreases IL-2, but not TNF-α, production induced by an anti-CD3 antibody in 50% whole blood and inhibits T cell proliferation in vitro in a mixed lymphocyte reaction assay (IC₅₀ = 30 nM). AMG 47a (10, 30, and 100 mg/kg) has anti-inflammatory activity, decreasing production of IL-2 induced by an anti-CD3 antibody in mice. It also decreases levels of mutant oncogene KRAS^G12V in HeLa cells in a reporter assay when used at a concentration of 1 µM.²

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1. DiMauro, E.F., Newcomb, J., Nunes, J.J., et al. Discovery of aminoquinazolines as potent, orally bioavailable inhibitors of Lck: Synthesis, SAR, and in vivo anti-inflammatory activity. J. Med. Chem. 49(19), 5671-5686 (2006).

2. Carver, J., Dexheimer, T.S., Hsu, D., et al. A high-throughput assay for small molecule destabilizers of the KRAS oncoprotein. PLoS One 9(8), e103836 (2014).