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Publication Abstract from PubMed

The RAS/RAF/MEK/ERK signaling pathway has been targeted with a number of small molecule inhibitors in oncology clinical development across multiple disease indications. Importantly, cell lines with acquired resistance to B-RAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition by small molecule inhibitors. There are a number of selective, non-covalent, ERK1/2 inhibitors reported along with the promiscuous hypothemycin (and related analogues) which act via a covalent mechanism of action. This manuscript reports the identification of multiple series of highly selective covalent ERK1/2 inhibitors informed by structure-based drug design (SBDD). As a starting point for these covalent inhibitors, both reported ERK1/2 inhibitors and chemical series identified via high-throughput screening, were exploited. These approaches resulted in the identification of selective covalent tool compounds for potential in vitro and in vivo studies to assess the risks and or benefits of targeting this pathway through such a mechanism of action.

Structure-guided Design of Highly Selective and Potent Covalent Inhibitors of ERK1/2.,Ward RA, Colclough N, Challinor M, Debreczeni J, Eckersley K, Fairley G, Feron L, Flemington V, Graham MA, Greenwood R, Hopcroft P, Howard TD, James M, Jones CD, Jones CR, Renshaw J, Roberts K, Snow L, Tonge M, Yeung K J Med Chem. 2015 May 15. PMID:25977981^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.