- Structure-Guided Design of Group i Selective p21-Activated Kinase Inhibitors
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The p21-activated kinases (PAKs) play important roles in cytoskeletal organization, cellular morphogenesis, and survival and have generated significant attention as potential therapeutic targets for cancer. Following a high-throughput screen, we identified an aminopyrazole scaffold-based series that was optimized to yield group I selective PAK inhibitors. A structure-based design effort aimed at targeting the ribose pocket for both potency and selectivity led to much-improved group I vs II selectivity. Early lead compounds contained a basic primary amine, which was found to be a major metabolic soft spot with in vivo clearance proceeding predominantly via N-acetylation. We succeeded in identifying replacements with improved metabolic stability, leading to compounds with lower in vivo rodent clearance and excellent group I PAK selectivity.
- Crawford, James J.,Lee, Wendy,Aliagas, Ignacio,Mathieu, Simon,Hoeflich, Klaus P.,Zhou, Wei,Wang, Weiru,Rouge, Lionel,Murray, Lesley,La, Hank,Liu, Ning,Fan, Peter W.,Cheong, Jonathan,Heise, Christopher E.,Ramaswamy, Sreemathy,Mintzer, Robert,Liu, Yanzhou,Chao, Qi,Rudolph, Joachim
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p. 5121 - 5136
(2015/07/02)
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- SERINE/THREONINE PAK1 INHIBITORS
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Compounds having the formula I wherein A, Z, R1a, R1b, R2, R3, R4, R5, R6, R7, R9, R10, Ra, Rb and n are as defined herein are inhibitors of PAK1. Also disclosed are compositions and methods for treating cancer and hyperproliferative disorders.
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Page/Page column 136
(2013/03/26)
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