GDC-0623

GDC-0623 is a potent, ATP-uncompetitive inhibitor of MEK1 (K_i = 0.13 nM in the presence of ATP). It inhibits the proliferation of A375 BRAF(V600E) and HCT116 KRAS(G13D)-mutant cancer cell lines with EC₅₀ values of 7 and 42 nM, respectively. GDC-0623 inhibits ERK and BIM phosphorylation resulting in upregulation and stabilization of pro-apoptotic BIM protein in KRAS mutant and wild-type HCT116 cells and in KRAS mutant GW620 cells.

GDC-0623 (RG 7421) is a potent, ATP-uncompetitive inhibitor of MEK1 (Ki=0.13 nM, +ATP), and displays 6-fold weaker potency against HCT116 (KRAS (G13D), EC50=42 nM) versus A375 (BRAFV600E, EC50=7 nM).

ChEBI: GDC-0623 is a member of the class of imidazopyridines that is imidazo[1,5-a]pyridine substituted by (2-fluoro-4-iodophenyl)amino and (2-hydroxyethoxy)aminoacyl groups at positions 5 and 6. It is a potent ATP non-competitive inhibitor of MEK1 (Ki = 0.13nM) and also has efficacy against both mutant BRAF and mutant KRAS. It is in clinical development for treatment of patients with locally advanced or metastatic solid tumors. It has a role as an EC 2.7.12.2 (mitogen-activated protein kinase kinase) inhibitor, an antineoplastic agent and an apoptosis inducer. It is a substituted aniline, a member of monofluorobenzenes, an organoiodine compound, an imidazopyridine, a secondary amino compound, a hydroxamic acid ester and a primary alcohol.

MEK1

MEK1: 0.13 nM (Ki, +ATP)

[1] hatzivassiliou g, haling j r, chen h, et al. mechanism of mek inhibition determines efficacy in mutant kras-versus braf-driven cancers. nature, 2013, 501(7466): 232-236.