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Discovery of a potent and selective oral inhibitor of ERK1/2 (AZD0364) that is efficacious in both monotherapy and combination therapy in models of non-small cell lung cancer (NSCLC)

DOI: 10.1021/acs.jmedchem.9b01295 DOI Help

Authors: Richard A Ward (AstraZeneca) , Mark J Anderton (AstraZeneca) , Paul A. Bethel (AstraZeneca) , Jason Breed (AstraZeneca) , Calum Cook (AstraZeneca) , Emma Davies (AstraZeneca) , Andrew Dobson (AstraZeneca) , Zhiqiang Dong (Pharmaron Beijing Co., Ltd) , Gary Fairley (AstraZeneca) , Paul Farrington (AstraZeneca) , Lyman J. Feron (AstraZeneca) , Vikki Flemington (AstraZeneca) , Francis D Gibbons (AstraZeneca) , Mark A. Graham (AstraZeneca) , Ryan David Robert Greenwood (AstraZeneca) , Lyndsey Hanson (AstraZeneca) , Philip Hopcroft (AstraZeneca) , Rachel Howells (AstraZeneca) , Julian Hudson (AstraZeneca) , Michael James (AstraZeneca) , Clifford D. Jones (AstraZeneca) , Christopher Jones (AstraZeneca) , Yongchao Li (Pharmaron Beijing Co., Ltd) , Scott Lamont (AstraZeneca) , Richard James Lewis (AstraZeneca) , Nicola A. Lindsay (AstraZeneca) , James Francis Mccabe (AstraZeneca) , Thomas M. Mcguire (AstraZeneca) , Philip B. Rawlins (AstraZeneca) , Karen Roberts (AstraZeneca) , Linda Sandin (AstraZeneca) , Iain Simpson (AstraZeneca) , Steve Swallow (AstraZeneca) , Jia Tang (Pharmaron Beijing Co., Ltd) , Gary Tomkinson (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: November 2019
Diamond Proposal Number(s): 20015 , 17180

Abstract: The RAS/MAPK pathway is a major driver of oncogenesis and is dysregulated in approximately 30% of human cancers, primarily by mutations in the BRAF or RAS genes. The extracellular-signal-regulated kinases (ERK1 and ERK2) serve as central nodes within this pathway. The feasibility of targeting the RAS/MAPK pathway has been demonstrated by the clinical responses observed through the use of BRAF and MEK inhibitors in BRAF V600E/K metastatic melanoma, however resistance frequently develops. Importantly, ERK1/2 inhibition may have clinical utility in overcoming acquired resistance to RAF and MEK inhibitors where RAS/MAPK pathway reactivation has occurred, such as relapsed BRAF V600E/K melanoma. We describe our structure-based design approach leading to the discovery of AZD0364, a potent and selective inhibitor of ERK1 and ERK2. AZD0364 exhibits high cellular potency (IC50 = 6 nM) and excellent physico-chemical and absorption, distribution, metabolism, and excretion (ADME) properties and has demonstrated encouraging anti-tumour activity in pre-clinical models.

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

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


Instruments: I04-Macromolecular Crystallography