Discovery of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine inhibitors of Erk2

The RAF-MEK-ERK Pathway: Targeting ERK to Overcome Obstacles of Effective Cancer Therapy

“…Recently, from dozens of tetrahydropyridopyrimidines, Blake et al reported the discovery and optimization of a potent and selective ERKi, compound 38, a novel ATP-competitive inhibitor [134]. In a panel of kinase inhibition ability, compound 38 could strongly inhibit ERK2 with IC 50 of 2 nM and showed high kinase selectivity, of which only 2 out of 170 were inhibited by greater than 75% at a test concentration of 100 nM.…”

Design, synthesis and biological evaluation of fused naphthofuro[3,2-c] quinoline-6,7,12-triones and pyrano[3,2-c]quinoline-6,7,8,13-tetraones derivatives as ERK inhibitors with efficacy in BRAF-mutant melanoma

“…[40]. Autodock performance was first validated on an ERK2 crystal structure in complex with a tetra-hydropyridopyrimidine amine derivative (N-[(1S)-1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl]-2-(tetrahydro-2H-pyran-4-ylamino)-5,8dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide) or 2SH that been reported previously as an ATP competitive inhibitor of ERK [41] (PDB code: 4O6E [41]). Self-docking of 2SH was performed and the corresponding binding mode was investigated.…”

Synthesis and antitumor evaluation of novel 4‐anilino‐7,8‐dihydropyrido[4,3‐d]pyrimidine‐6(5H)‐carboxylate derivatives as potential EGFR inhibitors

“…Dihydropyrido[4,3‐ d ]pyrimidine (DHPP) motif as “privileged medicinal scaffold” has attracted considerable attention due to their biological and pharmaceutical utilities, serving for the generation of small‐molecule ligands with pronounced anticancer, antidiabetes, or antischizophrenia efficacy, such as Erks inhibitor I and Bcl‐2 inhibitor II . DHPP retains the stability of the quinazoline, meanwhile, its 6‐substituted side chain showed more flexibility than quinazoline on account of fusing saturated tetrahydropyridine moiety.…”