Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 56, Issue 11, Pages 4413-4421Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm4000837
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Funding
- SGC [1097737]
- Canadian Institutes for Health Research
- Canada Foundation for Innovation
- Genome Canada
- GlaxoSmithKline
- Pfizer
- Eli Lilly
- Takeda
- AbbVie
- Novartis Research Foundation
- Ontario Ministry of Research and Innovation
- Wellcome Trust [092809/Z/10/Z]
- MRC [MC_U127081014, MC_UU_12016/10] Funding Source: UKRI
- Medical Research Council [MC_UU_12016/10, MC_U127081014, 999692] Funding Source: researchfish
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The protein kinase ERK5 (MAPK7) is an emerging drug target for a variety of indications, in particular for cancer where it plays a key role mediating cell proliferation, survival, epithelial-mesenchymal transition, and angiogenesis. To date, no three-dimensional structure has been published that would allow rational design of inhibitors. To address this, we determined the X-ray crystal structure of the human ERK5 kinase domain in complex with a highly specific benzo[e]pyrimido[5,4-b]diazepine-6(11H)-one inhibitor. The structure reveals that specific residue differences in the ATP-binding site, compared to the related ERKs p38s and JNKs, allow for the development of ERK5-specific inhibitors. The selectivity of previously observed ERK5 inhibitors can also be rationalized using this structure, which provides a template for future development of inhibitors with potential for treatment of disease.
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