Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development.
Binh Thanh Vu,Peter Michael Wovkulich,Giacomo Pizzolato,Allen John Lovey,Qingjie Ding,Nan Jiang,Jin-Jun Liu,Chunlin Zhao,Kelli Glenn,Yang Wen,Christian Tovar,Packman Kathryn E,Lyubomir T. Vassilev,Bradford Graves +13 more
TLDR
RG7112 is the first clinical small-molecule MDM2 inhibitor designed to occupy the p53-binding pocket ofMDM2, which stabilizes p53 and activates the p 53 pathway, leading to cell cycle arrest, apoptosis, and inhibition or regression of human tumor xenografts.Abstract:
The p53 tumor suppressor is a potent transcription factor that plays a key role in the regulation of cellular responses to stress It is controlled by its negative regulator MDM2, which binds directly to p53 and inhibits its transcriptional activity MDM2 also targets p53 for degradation by the proteasome Many tumors produce high levels of MDM2, thereby impairing p53 function Restoration of p53 activity by inhibiting the p53-MDM2 interaction may represent a novel approach to cancer treatment RG7112 (2g) is the first clinical small-molecule MDM2 inhibitor designed to occupy the p53-binding pocket of MDM2 In cancer cells expressing wild-type p53, RG7112 stabilizes p53 and activates the p53 pathway, leading to cell cycle arrest, apoptosis, and inhibition or regression of human tumor xenograftsread more
Citations
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Small-molecule inhibitors of the MDM2-p53 protein-protein interaction (MDM2 Inhibitors) in clinical trials for cancer treatment.
TL;DR: A review of the design, synthesis, properties, preclinical, and clinical studies of seven clinical-stage MDM2 inhibitors for the treatment of human cancers.
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References
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p53, the Cellular Gatekeeper for Growth and Division
TL;DR: The author regrets the lack of citations for many important observations mentioned in the text, but their omission is made necessary by restrictions in the preparation of review manuscripts.
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Surfing the p53 network
TL;DR: The p53 tumour-suppressor gene integrates numerous signals that control cell life and death, and the disruption of p53 has severe consequences when a highly connected node in the Internet breaks down.
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In vivo activation of the p53 pathway by small-molecule antagonists of MDM2.
Lyubomir T. Vassilev,Binh Thanh Vu,Bradford Graves,Daisy Carvajal,Frank John Podlaski,Zoran Filipovic,Norman Kong,Ursula Kammlott,Christine Lukacs,Christian Klein,Nader Fotouhi,Liu Emily Aijun +11 more
TL;DR: In this article, the authors identify potent and selective small-molecule antagonists of MDM2 and confirm their mode of action through the crystal structures of complexes, leading to cell cycle arrest, apoptosis, and growth inhibition of human tumor xenografts.
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Regulation of p53 stability by Mdm2
TL;DR: It is shown that interaction with Mdm2 can also result in a large reduction in p53 protein levels through enhanced proteasome-dependent degradation, which may contribute to the maintenance of low p53 concentrations in normal cells.
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The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation
TL;DR: A product of the mdm-2 oncogene forms a tight complex with the p53 protein, and the mDM-2oncogene can inhibit p53-mediated transactivation.