7n3u
Crystal structure of human WEE1 kinase domain in complex with ZN-c3
Structural highlights
FunctionWEE1_HUMAN Acts as a negative regulator of entry into mitosis (G2 to M transition) by protecting the nucleus from cytoplasmically activated cyclin B1-complexed CDK1 before the onset of mitosis by mediating phosphorylation of CDK1 on 'Tyr-15'. Specifically phosphorylates and inactivates cyclin B1-complexed CDK1 reaching a maximum during G2 phase and a minimum as cells enter M phase. Phosphorylation of cyclin B1-CDK1 occurs exclusively on 'Tyr-15' and phosphorylation of monomeric CDK1 does not occur. Its activity increases during S and G2 phases and decreases at M phase when it is hyperphosphorylated. A correlated decrease in protein level occurs at M/G1 phase, probably due to its degradation. Publication Abstract from PubMedWee1 inhibition has received great attention in the past decade as a promising therapy for cancer treatment. Therefore, a potent and selective Wee1 inhibitor is highly desirable. Our efforts to make safer and more efficacious Wee1 inhibitors led to the discovery of compound 16, a highly selective Wee1 inhibitor with balanced potency, ADME, and pharmacokinetic properties. The chiral ethyl moiety of compound 16 provided an unexpected improvement of Wee1 potency. Compound 16, known as ZN-c3, showed excellent in vivo efficacy and is currently being evaluated in phase 2 clinical trials. Discovery of ZN-c3, a Highly Potent and Selective Wee1 Inhibitor Undergoing Evaluation in Clinical Trials for the Treatment of Cancer.,Huang PQ, Boren BC, Hegde SG, Liu H, Unni AK, Abraham S, Hopkins CD, Paliwal S, Samatar AA, Li J, Bunker KD J Med Chem. 2021 Sep 9;64(17):13004-13024. doi: 10.1021/acs.jmedchem.1c01121., Epub 2021 Aug 23. PMID:34423975[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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