Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition
Sanjeev Shangary,Dongguang Qin,Donna McEachern,Meilan Liu,Rebecca Miller,Su Qiu,Zaneta Nikolovska-Coleska,Ke Ding,Guoping Wang,Jianyong Chen,Denzil Bernard,Jian Zhang,Yipin Lu,Qingyang Gu,Rajal B. Shah,Kenneth J. Pienta,Xiaolan Ling,Sanmao Kang,Ming Guo,Yi Sun,Dajun Yang,Shaomeng Wang +21 more
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TLDR
MI-219 stimulates rapid but transient p53 activation in established tumor xenograft tissues, resulting in inhibition of cell proliferation, induction of apoptosis, and complete tumor growth inhibition.Abstract:
We have designed MI-219 as a potent, highly selective and orally active small-molecule inhibitor of the MDM2–p53 interaction. MI-219 binds to human MDM2 with a Ki value of 5 nM and is 10,000-fold selective for MDM2 over MDMX. It disrupts the MDM2–p53 interaction and activates the p53 pathway in cells with wild-type p53, which leads to induction of cell cycle arrest in all cells and selective apoptosis in tumor cells. MI-219 stimulates rapid but transient p53 activation in established tumor xenograft tissues, resulting in inhibition of cell proliferation, induction of apoptosis, and complete tumor growth inhibition. MI-219 activates p53 in normal tissues with minimal p53 accumulation and is not toxic to animals. MI-219 warrants clinical investigation as a new agent for cancer treatment.read more
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Apoptosis in cancer: from pathogenesis to treatment
TL;DR: The abundance of literature suggests that targeting apoptosis in cancer is feasible, however, many troubling questions arise with the use of new drugs or treatment strategies that are designed to enhance apoptosis and critical tests must be passed before they can be used safely in human subjects.
Journal ArticleDOI
Modes of p53 regulation.
Jan Philipp Kruse,Wei Gu +1 more
TL;DR: It is proposed that antirepression, the release of p53 from repression by factors such as Mdm2 and MdmX, is a key step in the physiological activation of p 53.
Journal ArticleDOI
Awakening guardian angels: drugging the p53 pathway
TL;DR: Several original approaches to drug discovery that could have wide applications to drug development are being used, including molecules that activate p53 by blocking protein–protein interactions with MDM2 and p53-binding molecules that can rescue the function of certain p53 mutants.
Journal ArticleDOI
Brønsted-Acid-Catalyzed Asymmetric Multicomponent Reactions for the Facile Synthesis of Highly Enantioenriched Structurally Diverse Nitrogenous Heterocycles
Jie Yu,Feng Shi,Liu-Zhu Gong +2 more
TL;DR: A detailed investigation of several MCRs catalyzed by chiral phosphoric acids that lead to the production of structurally diverse nitrogenous heterocycles is presented, including Biginelli and Biginelli-like reactions; 1,3-dipolar cycloadditions; aza Diels-Alder reactions; and some other cyclization reactions.
Journal ArticleDOI
Organocatalytic Asymmetric Assembly Reactions: Synthesis of Spirooxindoles via Organocascade Strategies
TL;DR: This review focuses on the enantioselective synthesis of spirooxindoles via organocascade strategies and is organized on the basis of three primary starting materials and then further subdivided according to the types of organocatalyst.
References
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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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A System for Stable Expression of Short Interfering RNAs in Mammalian Cells
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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.
Journal ArticleDOI
Live or let die: the cell's response to p53
Karen H. Vousden,Xin Lu +1 more
TL;DR: Understanding the complex mechanisms that regulate whether or not a cell dies in response to p53 will ultimately contribute to the development of therapeutic strategies to repair the apoptotic p53 response in cancers.