1. Discovery of a Potent and Selective Oral Inhibitor of ERK1/2 (AZD0364) That Is Efficacious in Both Monotherapy and Combination Therapy in Models of Nonsmall Cell Lung Cancer (NSCLC)
- Author
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Jia Tang, Richard A. Ward, Paul A. Bethel, Scott G. Lamont, Julian A. Hudson, Philip Hopcroft, Clifford David Jones, Steve Swallow, Richard J. Lewis, Tomkinson Gary Peter, Baochang Zhai, Nicola Lindsay, Jason Breed, Emma J. Davies, Yongchao Li, Vikki Flemington, Michael Tonge, Paul Farrington, Ryan Greenwood, Mark A. Graham, Linda Sandin, Thomas M. McGuire, James F. McCabe, Mark J. Anderton, Michael R. James, Andrew Hornby Dobson, Philip B. Rawlins, Lyndsey Hanson, Iain Simpson, Karen Roberts, Gary Fairley, Rachel L. Howells, Christopher R. Jones, Calum Cook, Francis D. Gibbons, Zhiqiang Dong, Lyman Feron, and Zhenhua Wang
- Subjects
MAPK/ERK pathway ,Lung Neoplasms ,Combination therapy ,Administration, Oral ,Mice, Nude ,Antineoplastic Agents ,Apoptosis ,medicine.disease_cause ,01 natural sciences ,03 medical and health sciences ,Mice ,Carcinoma, Non-Small-Cell Lung ,Drug Discovery ,medicine ,Tumor Cells, Cultured ,Animals ,Humans ,Protein Kinase Inhibitors ,030304 developmental biology ,ADME ,Cell Proliferation ,Mitogen-Activated Protein Kinase 1 ,0303 health sciences ,Mitogen-Activated Protein Kinase 3 ,Molecular Structure ,Cell growth ,Chemistry ,Kinase ,Drug discovery ,Melanoma ,Imidazoles ,medicine.disease ,Xenograft Model Antitumor Assays ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Pyrimidines ,Pyrazines ,Cancer research ,Molecular Medicine ,Drug Therapy, Combination ,Female ,Carcinogenesis - 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) as well as excellent physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties and has demonstrated encouraging antitumor activity in preclinical models.
- Published
- 2019