title: Structure-Guided Design of Group I Selective p21-Activated Kinase Inhibitors.
abstract: 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.
authors.forename: James J
authors.initials: JJ
authors.lastname: Crawford
authors.forename: Wendy
authors.initials: W
authors.lastname: Lee
authors.forename: Ignacio
authors.initials: I
authors.lastname: Aliagas
authors.forename: Simon
authors.initials: S
authors.lastname: Mathieu
authors.forename: Klaus P
authors.initials: KP
authors.lastname: Hoeflich
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang
authors.forename: Lionel
authors.initials: L
authors.lastname: Rouge
authors.forename: Lesley
authors.initials: L
authors.lastname: Murray
authors.forename: Hank
authors.initials: H
authors.lastname: La
authors.forename: Ning
authors.initials: N
authors.lastname: Liu
authors.forename: Peter W
authors.initials: PW
authors.lastname: Fan
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cheong
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Heise
authors.forename: Sreemathy
authors.initials: S
authors.lastname: Ramaswamy
authors.forename: Robert
authors.initials: R
authors.lastname: Mintzer
authors.forename: Yanzhou
authors.initials: Y
authors.lastname: Liu
authors.affiliation: #Shanghai Chempartner Inc., 998 Halei Road, Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai 201203, People's Republic of China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Chao
authors.forename: Joachim
authors.initials: J
authors.lastname: Rudolph
mesh_terms: D000818:Animals; D015195:Drug Design; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: C436945:3-aminopyrazole; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D054462:p21-Activated Kinases