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: James J Crawford, Wendy Lee, Ignacio Aliagas, Simon Mathieu, Klaus P Hoeflich, Wei Zhou, Weiru Wang, Lionel Rouge, Lesley Murray, Hank La, Ning Liu, Peter W Fan, Jonathan Cheong, Christopher E Heise, Sreemathy Ramaswamy, Robert Mintzer, Yanzhou Liu, Qi Chao, Joachim Rudolph
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 12 Pg. 5121-36 (Jun 25 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 26030457 (Publication Type: Journal Article)

Chemical References

• 3-aminopyrazole
• Protein Kinase Inhibitors
• Pyrazoles
• p21-Activated Kinases

Topics

• Animals
• Drug Design
• Humans
• Mice
• Molecular Docking Simulation
• Protein Kinase Inhibitors (chemistry, pharmacokinetics, pharmacology)
• Pyrazoles (chemistry, pharmacokinetics, pharmacology)
• Rats
• p21-Activated Kinases (antagonists & inhibitors, chemistry, metabolism)