1. Structure-Guided Design ofHighly Selective and PotentCovalent Inhibitors of ERK1/2.
- Author
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Richard A. Ward, Nicola Colclough, Mairi Challinor, JuditE. Debreczeni, Kay Eckersley, Gary Fairley, Lyman Feron, Vikki Flemington, Mark A. Graham, Ryan Greenwood, Philip Hopcroft, Tina D. Howard, Michael James, Clifford D. Jones, Christopher R. Jones, Jonathan Renshaw, Karen Roberts, Lindsay Snow, Michael Tonge, and Kay Yeung
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STRUCTURE-activity relationship in pharmacology , *COVALENT bonds , *ENZYME inhibitors , *SMALL molecules , *DRUG use testing - Abstract
The RAS/RAF/MEK/ERK signaling pathwayhas been targeted with anumber of small molecule inhibitors in oncology clinical developmentacross multiple disease indications. Importantly, cell lines withacquired resistance to B-RAF and MEK inhibitors have been shown tomaintain sensitivity to ERK1/2 inhibition by small molecule inhibitors.There are a number of selective, noncovalent ERK1/2 inhibitors reportedalong with the promiscuous hypothemycin (and related analogues) thatact via a covalent mechanism of action. This article reports the identificationof multiple series of highly selective covalent ERK1/2 inhibitorsinformed by structure-based drug design (SBDD). As a starting pointfor these covalent inhibitors, reported ERK1/2 inhibitors and a chemicalseries identified via high-throughput screening were exploited. Theseapproaches resulted in the identification of selective covalent toolcompounds for potential in vitroand in vivostudies to assess the risks and or benefits of targeting this pathwaythrough such a mechanism of action. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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