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Publication Abstract from PubMed

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.

Structure-Guided Design of Group I Selective p21-Activated Kinase Inhibitors.,Crawford JJ, Lee W, Aliagas I, Mathieu S, Hoeflich KP, Zhou W, Wang W, Rouge L, Murray L, La H, Liu N, Fan PW, Cheong J, Heise CE, Ramaswamy S, Mintzer R, Liu Y, Chao Q, Rudolph J J Med Chem. 2015 Jun 25;58(12):5121-36. doi: 10.1021/acs.jmedchem.5b00572. Epub, 2015 Jun 12. PMID:26030457^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.