Journal of Medicinal Chemistry p. 11004 - 11018 (2019)
Update date:2022-08-15
Topics:
Ward, Richard A.
Anderton, Mark J.
Bethel, Paul
Breed, Jason
Cook, Calum
Davies, Emma J.
Dobson, Andrew
Dong, Zhiqiang
Fairley, Gary
Farrington, Paul
Feron, Lyman
Flemington, Vikki
Gibbons, Francis D.
Graham, Mark A.
Greenwood, Ryan
Hanson, Lyndsey
Hopcroft, Philip
Howells, Rachel
Hudson, Julian
James, Michael
Jones, Clifford D.
Jones, Christopher R.
Li, Yongchao
Lamont, Scott
Lewis, Richard
Lindsay, Nicola
McCabe, James
McGuire, Thomas
Rawlins, Philip
Roberts, Karen
Sandin, Linda
Simpson, Iain
Swallow, Steve
Tang, Jia
Tomkinson, Gary
Tonge, Michael
Wang, Zhenhua
Zhai, Baochang
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) as well as excellent physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties and has demonstrated encouraging antitumor activity in preclinical models.
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