title: p21-Activated kinase inhibitors: a patent review.
abstract: BACKGROUND
  The p21-activated kinase (PAK) family of serine/threonine protein kinases is activated by binding to the small (p21) GTP-binding proteins Cdc42 and Rac. The PAK family plays important roles in cytoskeletal organisation, cellular morphogenesis and survival, and members of this family have been implicated in a wide range of diseases including cancer, infectious diseases, neurological disorders and arthritis.
  
  
  METHODS
  The present review seeks to summarise recent (up to 2011) reports of small-molecule inhibitors of p21-activated kinases. Where patent applications describe activity against a broad range of kinases and no information was provided specifically on PAK inhibition, these are excluded from this review. In patents considered to be relevant, exemplary compounds were selected and highlighted based on their representation of the chemical matter claimed, potencies, structural features and subsequent disclosure of their properties. Selected information from non-patent literature was also included.
  
  
  CONCLUSIONS
  A considerable amount of research has been devoted over the past 15 years to exploring the role of PAKs in a wide range of diseases, with a focus on oncology. Published PAK inhibitors are still comparatively rare and few exhibit satisfactory kinase selectivity and 'drug-like' properties. A key question is which profile, pan-PAK, group selective or isoform selective, holds the most promise from both therapeutic and safety standpoints. To investigate this question, isoform-selective, as well as kinome-selective, PAK inhibitor tool compounds will be needed. Pfizer was the first company to progress a PAK inhibitor (pan-PAK) to clinical development; it is expected that, despite the difficulties, other PAK inhibitors will soon follow.
authors.affiliation: Department of Discovery Chemistry, Genentech, Inc., South San Francisco, CA 94080, USA. crawford.james@gene.com
authors.forename: James J
authors.initials: JJ
authors.lastname: Crawford
authors.forename: Klaus P
authors.initials: KP
authors.lastname: Hoeflich
authors.forename: Joachim
authors.initials: J
authors.lastname: Rudolph
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D010330:Patents as Topic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D054462:p21-Activated Kinases; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins