Structure-Guided Discovery of Potent and Selective Inhibitors of ERK1/2 from a Modestly Active and Promiscuous Chemical Start Point.
Basic Information
ID: ALA4049432
Journal: J Med Chem
Title: Structure-Guided Discovery of Potent and Selective Inhibitors of ERK1/2 from a Modestly Active and Promiscuous Chemical Start Point.
Authors: Ward RA, Bethel P, Cook C, Davies E, Debreczeni JE, Fairley G, Feron L, Flemington V, Graham MA, Greenwood R, Griffin N, Hanson L, Hopcroft P, Howard TD, Hudson J, James M, Jones CD, Jones CR, Lamont S, Lewis R, Lindsay N, Roberts K, Simpson I, St-Gallay S, Swallow S, Tang J, Tonge M, Wang Z, Zhai B.
Abstract: There are a number of small-molecule inhibitors targeting the RAS/RAF/MEK/ERK signaling pathway that have either been approved or are in clinical development for oncology across a range of disease indications. The inhibition of ERK1/2 is of significant current interest, as cell lines with acquired resistance to BRAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition in preclinical models. This article reports on our recent work to identify novel, potent, and selective reversible ERK1/2 inhibitors from a low-molecular-weight, modestly active, and highly promiscuous chemical start point, compound 4. To guide and inform the evolution of this series, inhibitor binding mode information from X-ray crystal structures was critical in the rapid exploration of this template to compound 35, which was active when tested in in vivo antitumor efficacy experiments.
CiteXplore: 28376306
DOI: 10.1021/acs.jmedchem.7b00267
Patent ID: ┄