Michael D Wendt1. 1. Abbott Laboratories, Cancer Research, Global Pharmaceutical R&D, Dept R4N6, Bldg. AP10-3, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA +1 847 937 9305 ; +1 847 938 1004 ; mike.d.wendt@abbott.com.
Abstract
BACKGROUND: The discovery of ABT-263, a rationally designed Bcl-2/Bcl-xL inhibitor at present in Phase I clinical trials for cancer, is described. Emphasis is placed on the specific hurdles overcome throughout the discovery process that relate to the nature of the targeted protein-protein interaction (PPI). OBJECTIVE/ METHODS: This review draws on observations from the experience of discovering ABT-263 and discusses them within the framework of the larger issue of discovering drugs targeting PPIs. Issues discussed include the 'hot spot' paradigm, hit and lead generation, serum protein binding, structure-based design, and in particular, hydrophobicity and molecular size and their relation to pharmacokinetic/pharmacodynamic properties. RESULTS/ CONCLUSION: Approaches to understanding obstacles thought of as being specifically attached to PPIs, and existing techniques to combat these obstacles, were very helpful in overcoming them. The example of ABT-263 provides evidence that the larger family of PPI targets is more tractable than may have been thought.
BACKGROUND: The discovery of ABT-263, a rationally designed Bcl-2/Bcl-xL inhibitor at present in Phase I clinical trials for cancer, is described. Emphasis is placed on the specific hurdles overcome throughout the discovery process that relate to the nature of the targeted protein-protein interaction (PPI). OBJECTIVE/ METHODS: This review draws on observations from the experience of discovering ABT-263 and discusses them within the framework of the larger issue of discovering drugs targeting PPIs. Issues discussed include the 'hot spot' paradigm, hit and lead generation, serum protein binding, structure-based design, and in particular, hydrophobicity and molecular size and their relation to pharmacokinetic/pharmacodynamic properties. RESULTS/ CONCLUSION: Approaches to understanding obstacles thought of as being specifically attached to PPIs, and existing techniques to combat these obstacles, were very helpful in overcoming them. The example of ABT-263 provides evidence that the larger family of PPI targets is more tractable than may have been thought.
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Authors: 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; Sarah G Hymowitz; Sha Jin; Seong Lin Khaw; Peter J Kovar; Lloyd T Lam; Jackie Lee; Heather L Maecker; Kennan C Marsh; Kylie D Mason; Michael J Mitten; Paul M Nimmer; Anatol Oleksijew; Chang H Park; Cheol-Min Park; Darren C Phillips; Andrew W Roberts; Deepak Sampath; John F Seymour; Morey L Smith; Gerard M Sullivan; Stephen K Tahir; Chris Tse; Michael D Wendt; Yu Xiao; John C Xue; Haichao Zhang; Rod A Humerickhouse; Saul H Rosenberg; Steven W Elmore Journal: Nat Med Date: 2013-01-06 Impact factor: 53.440
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Authors: Paulo H C Godoi; Rachel P Wilkie-Grantham; Asami Hishiki; Renata Sano; Yasuko Matsuzawa; Hiroko Yanagi; Claudia E Munte; Ya Chen; Yong Yao; Francesca M Marassi; Hans R Kalbitzer; Shu-Ichi Matsuzawa; John C Reed Journal: J Biol Chem Date: 2016-04-19 Impact factor: 5.157