Small-molecule inhibitors of protein-protein interactions: progressing toward the reality.
TLDR
The past 20 years have seen many advances in understanding of protein-protein interactions (PPIs) and how to target them with small-molecule therapeutics; since then, potent inhibitors have been developed for diverse protein complexes, and compounds are now in clinical trials for six targets.About:
This article is published in Chemistry & Biology.The article was published on 2014-09-18 and is currently open access. It has received 834 citations till now.read more
Citations
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Small molecules, big targets: drug discovery faces the protein–protein interaction challenge
TL;DR: The research leading to breakthroughs in PPI inhibition is described and the existence of groups of structurally related PPIs within the PPI target class is highlighted to illustrate the research strategies that have proved most useful.
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Targeting transcription factors in cancer - from undruggable to reality.
TL;DR: This Review discusses the various approaches that are being explored to target transcription factors in cancer, with many of the inhibitors developed from such approaches now advancing to early clinical trials.
Journal ArticleDOI
Rule of five in 2015 and beyond: Target and ligand structural limitations, ligand chemistry structure and drug discovery project decisions☆
TL;DR: The rule of five (Ro5), based on physicochemical profiles of phase II drugs, is consistent with structural limitations in protein targets and the drug target ligands and is a strong contributor to NP Ro5 outliers.
Journal ArticleDOI
Tranilast directly targets NLRP3 to treat inflammasome-driven diseases.
Yi Huang,Hua Jiang,Yun Chen,Xiaqiong Wang,Yanqing Yang,Jinhui Tao,Xianming Deng,Gaolin Liang,Huafeng Zhang,Wei Jiang,Rongbin Zhou +10 more
TL;DR: In vivo experiments show that tranilast has remarkable preventive or therapeutic effects on the mouse models of NLRP3 inflammasome‐related human diseases, including gouty arthritis, cryopyrin‐associated autoinflammatory syndromes, and type 2 diabetes.
Journal ArticleDOI
Biophysics in drug discovery: impact, challenges and opportunities
Jean-Paul Renaud,Chun-wa Chung,U. Helena Danielson,Ursula Egner,Michael Hennig,Roderick E. Hubbard,Herbert Nar +6 more
TL;DR: This Review provides a framework to understand this evolution of biophysical technologies by describing the key biophysical methods, the information they can provide and the ways in which they can be applied at different stages of the drug discovery process.
References
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In vivo activation of the p53 pathway by small-molecule antagonists of MDM2.
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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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TL;DR: A cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains is reported, establishing proof-of-concept for targeting protein–protein interactions of epigenetic ‘readers’, and providing a versatile chemical scaffold for the development of chemical probes more broadly throughout the b romodomain family.
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Andrew J. Souers,Joel D. Leverson,Erwin R. Boghaert,Scott L. Ackler,Nathaniel D. Catron,Jun Chen,Brian D. Dayton,Hong Ding,Sari H. Enschede,Wayne J. Fairbrother,David C.S. Huang,David C.S. Huang,Sarah G. Hymowitz,Sha Jin,Seong Lin Khaw,Seong Lin Khaw,Peter Kovar,Lloyd T. Lam,Jackie Lee,Heather Maecker,Kennan C. Marsh,Kylie D. Mason,Kylie D. Mason,Kylie D. Mason,Michael J. Mitten,Paul Nimmer,Anatol Oleksijew,Chang H. Park,Cheol-Min Park,Cheol-Min Park,Darren C. Phillips,Andrew W. Roberts,Andrew W. Roberts,Andrew W. Roberts,Deepak Sampath,John F. Seymour,John F. Seymour,Morey L. Smith,Gerard M. Sullivan,Stephen K. Tahir,Chris Tse,Michael D. Wendt,Yu Xiao,John Xue,Haichao Zhang,Rod A. Humerickhouse,Saul H. Rosenberg,Steven W. Elmore +47 more
TL;DR: The re-engineering of navitoclax is reported to create a highly potent, orally bioavailable and BCL-2–selective inhibitor, ABT-199, which inhibits the growth of BCL–dependent tumors in vivo and spares human platelets, indicating that selective pharmacological inhibition of Bcl-2 shows promise for the treatment of B CL-2-dependent hematological cancers.
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Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain.
Paul H. Kussie,Svetlana Gorina,Vincent Marechal,Brian Elenbaas,Jacque Moreau,Arnold J. Levine,Nikola P. Pavletich +6 more
TL;DR: The crystal structure of the 109-residue amino-terminal domain of MDM2 bound to a 15-Residue transactivation domain peptide of p53 revealed that MDM 2 has a deep hydrophobic cleft on which the p53 peptide binds as an amphipathic α helix, supporting the hypothesis thatMDM2 inactivates p53 by concealing its transactivationdomain.
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