MGCD-265

MGCD-265 is an inhibitor of c-Met and VEGFR2 (IC₅₀s = 0.029 and 0.01 µM, respectively).¹ It is selective for c-Met and VEGFR2 over Chk1, EGFR, GSK3β, IGF-1R, IKKβ, JAK2, and JNK1 at 0.1 µM but also inhibits VEGFR1, VEGFR3, Ron, Tie2, FLT3, c-Kit, Abl, and TrkA with percent inhibition values ranging from 80 to 100% at 0.1 µM. MGCD-265 also binds to Smoothened (Smo) in HEK293T cell membranes expressing the human receptor (K_i = 0.0417 µM for the wild-type receptor) and inhibits Gli1-mediated transcription in a reporter assay in gefitinib-resistant HCC827 non-small cell lung cancer (NSCLC) cells.² It inhibits migration of A549 NSCLC cells induced by hepatocyte growth factor (HGF) and VEGF-induced proliferation of human umbilical vein endothelial cells (HUVECs; IC₅₀s = 2 and 0.025 µM, respectively).¹ MGCD-265 (20 mg/kg) reduces tumor growth in several mouse xenograft models, including prostate, colorectal, and gastric cancer models.

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1. Claridge, S., Raeppel, F., Granger, M.-C., et al. Discovery of a novel and potent series of thieno[3,2-b]pyridine-based inhibitors of c-Met and VEGFR2 tyrosine kinases. Bioorg. Med. Chem. Lett. 18(9), 2793-2798 (2008).

2. Morgillo, F., Amendola, G., Corte, C.M.D., et al. Dual MET and SMO negative modulators overcome resistance to EGFR inhibitors in human nonsmall cell lung cancer. J. Med. Chem. 60(17), 7447-7458 (2017).