作者
Richard A Ward, Mark J Anderton, Paul Bethel, Jason Breed, Calum Cook, Emma J Davies, Andrew Dobson, Zhiqiang Dong, Gary Fairley, Paul Farrington, Lyman Feron, Vikki Flemington, Francis D Gibbons, Mark A Graham, Ryan Greenwood, Lyndsey Hanson, Philip Hopcroft, Rachel Howells, Julian Hudson, Michael James, Clifford D Jones, Christopher R Jones, Yongchao Li, Scott Lamont, Richard Lewis, Nicola Lindsay, James McCabe, Thomas McGuire, Philip Rawlins, Karen Roberts, Linda Sandin, Iain Simpson, Steve Swallow, Jia Tang, Gary Tomkinson, Michael Tonge, Zhenhua Wang, Baochang Zhai
发表日期
2019/11/11
来源
Journal of medicinal chemistry
卷号
62
期号
24
页码范围
11004-11018
出版商
American Chemical Society
简介
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 …
学术搜索中的文章
RA Ward, MJ Anderton, P Bethel, J Breed, C Cook… - 2019