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Structure-Guided Discovery of Potent and Selective Inhibitors of ERK1/2 from a Modestly Active and Promiscuous Chemical Start Point

DOI: 10.1021/acs.jmedchem.7b00267 DOI Help

Authors: Richard A Ward (AstraZeneca) , Paul A. Bethel (AstraZeneca) , Calum Cook (AstraZeneca) , Emma Davies (AstraZeneca) , Judit E. Debreczeni (AstraZeneca) , Gary Fairley (AstraZeneca) , Lyman Feron (AstraZeneca) , Vikki Flemington (AstraZeneca) , Mark A. Graham , Ryan Greenwood (AstraZeneca) , Nicola Griffin (AstraZeneca) , Lyndsey Hanson (AstraZeneca) , Philip Hopcroft (AstraZeneca) , Tina D. Howard (AstraZeneca) , Julian Hudson (AstraZeneca) , Michael James (AstraZeneca) , Clifford D. Jones (AstraZeneca) , Christopher R Jones (Former employee of AstraZeneca) , Scott Lamont (AstraZeneca) , Richard James Lewis (AstraZeneca) , Nicola Lindsay (AstraZeneca) , Karen Roberts (AstraZeneca) , Iain Simpson (AstraZeneca) , Steve St-gallay (AstraZeneca) , Steve Swallow (AstraZeneca) , Jia Tang (AstraZeneca) , Michael Tonge (AstraZeneca) , Zhenhua Wang (Pharmaron Beijing Co., Ltd) , Baochang Zhai (Pharmaron Beijing Co., Ltd)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: April 2017

Abstract: There are a number of small molecule inhibitors targeting the RAS/RAF/MEK/ERK signaling pathway either approved or 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 pre-clinical models. This manuscript 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 starting point 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 anti tumour efficacy experiments.

Journal Keywords: ERK1/2; inhibitors; RAS/RAF/MEK/ERK signaling pathway; structure-based drug design; SBDD; oncology

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


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