Back pocket flexibility provides group II p21-activated kinase (PAK) selectivity for type I 1/2 kinase inhibitors.

Structure-based methods were used to design a potent and highly selective group II p21-activated kinase (PAK) inhibitor with a novel binding mode, compound 17. Hydrophobic interactions within a lipophilic pocket past the methionine gatekeeper of group II PAKs approached by these type I 1/2 binders were found to be important for improving potency. A structure-based hypothesis and strategy for achieving selectivity over group I PAKs, and the broad kinome, based on unique flexibility of this lipophilic pocket, is presented. A concentration-dependent decrease in tumor cell migration and invasion in two triple-negative breast cancer cell lines was observed with compound 17.

[1]  S. Licciulli,et al.  FRAX597, a Small Molecule Inhibitor of the p21-activated Kinases, Inhibits Tumorigenesis of Neurofibromatosis Type 2 (NF2)-associated Schwannomas* , 2013, The Journal of Biological Chemistry.

[2]  F. Gnad,et al.  Systems-wide Analysis of K-Ras, Cdc42, and PAK4 Signaling by Quantitative Phosphoproteomics* , 2013, Molecular & Cellular Proteomics.

[3]  Guomin Yao,et al.  N-substituted azaindoles as potent inhibitors of Cdc7 kinase. , 2013, Bioorganic & medicinal chemistry letters.

[4]  O. Plotnikova,et al.  Inhibiting NF-κB-inducing kinase (NIK): discovery, structure-based design, synthesis, structure-activity relationship, and co-crystal structures. , 2013, Bioorganic & medicinal chemistry letters.

[5]  A. Massey,et al.  Knockdown of PAK4 or PAK1 Inhibits the Proliferation of Mutant KRAS Colon Cancer Cells Independently of RAF/MEK/ERK and PI3K/AKT Signaling , 2012, Molecular Cancer Research.

[6]  A. Kalgutkar,et al.  Reactive Drug Metabolites: KALGUTKAR:REACTIVE METAB. , 2012 .

[7]  Adam R. Johnson,et al.  The crystal structure of the catalytic domain of the NF-κB inducing kinase reveals a narrow but flexible active site. , 2012, Structure.

[8]  D. Bouzida,et al.  Discovery of pyrroloaminopyrazoles as novel PAK inhibitors. , 2012, Journal of medicinal chemistry.

[9]  M. Belvin,et al.  Active PI3K Pathway Causes an Invasive Phenotype Which Can Be Reversed or Promoted by Blocking the Pathway at Divergent Nodes , 2012, PloS one.

[10]  A. Minden.  PAK4–6 in cancer and neuronal development , 2012, Cellular logistics.

[11]  M. Cheng,et al.  LCH-7749944, a novel and potent p21-activated kinase 4 inhibitor, suppresses proliferation and invasion in human gastric cancer cells. , 2012, Cancer letters.

[12]  K. Hoeflich,et al.  p21-Activated kinase inhibitors: a patent review , 2012, Expert opinion on therapeutic patents.

[13]  A. Minden,et al.  A key role for Pak4 in proliferation and differentiation of neural progenitor cells. , 2011, Developmental biology.

[14]  M. Angiolini.  Targeting the DFG-in kinase conformation: a new trend emerging from a patent analysis. , 2011, Future medicinal chemistry.

[15]  D. Knighton,et al.  Small-molecule p21-activated kinase inhibitor PF-3758309 is a potent inhibitor of oncogenic signaling and tumor growth , 2010, Proceedings of the National Academy of Sciences.

[16]  E. Casale,et al.  Through the "gatekeeper door": exploiting the active kinase conformation. , 2010, Journal of medicinal chemistry.

[17]  D. Heerding,et al.  Aminofurazans as potent inhibitors of AKT kinase. , 2009, Bioorganic & medicinal chemistry letters.

[18]  J. Barnier,et al.  PAK signalling in neuronal physiology. , 2009, Cellular signalling.

[19]  Gerald C. Chu,et al.  Genomic alterations link Rho family of GTPases to the highly invasive phenotype of pancreas cancer , 2008, Proceedings of the National Academy of Sciences.

[20]  J. Kendall,et al.  Copy number alterations in pancreatic cancer identify recurrent PAK4 amplification , 2008, Cancer biology & therapy.

[21]  Michelle Jobes,et al.  Targeted disruption of the Pak5 and Pak6 genes in mice leads to deficits in learning and locomotion. , 2008, Developmental biology.

[22]  G. Warren,et al.  Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase. , 2008, Journal of medicinal chemistry.

[23]  A. Minden,et al.  The Pak4 Protein Kinase Plays a Key Role in Cell Survival and Tumorigenesis in Athymic Mice , 2008, Molecular Cancer Research.

[24]  Luis E. Arias-Romero,et al.  A tale of two Paks , 2008, Biology of the cell.

[25]  Suzanne Schubbert,et al.  Hyperactive Ras in developmental disorders and cancer , 2007, Nature Reviews Cancer.

[26]  C. Liang,et al.  In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro , 2007, Nature Protocols.

[27]  Anupama E. Gururaj,et al.  p21-activated kinases in cancer , 2006, Nature Reviews Cancer.

[28]  A. Minden,et al.  Pak4 Induces Premature Senescence via a Pathway Requiring p16INK4/p19ARF and Mitogen-Activated Protein Kinase Signaling , 2005, Molecular and Cellular Biology.

[29]  J. Ptak,et al.  Colorectal cancer: Mutations in a signalling pathway , 2005, Nature.

[30]  M. Gishizky,et al.  PAK4 mediates morphological changes through the regulation of GEF-H1 , 2005, Journal of Cell Science.

[31]  D. Whyte,et al.  Requirement for PAK4 in the Anchorage-independent Growth of Human Cancer Cell Lines* , 2002, The Journal of Biological Chemistry.

[32]  O. Bernard,et al.  Cytoskeletal Changes Regulated by the PAK4 Serine/Threonine Kinase Are Mediated by LIM Kinase 1 and Cofilin* , 2001, The Journal of Biological Chemistry.

[33]  A. Minden,et al.  Activated PAK4 Regulates Cell Adhesion and Anchorage-Independent Growth , 2001, Molecular and Cellular Biology.

[34]  N. Gnesutta,et al.  The Serine/Threonine Kinase PAK4 Prevents Caspase Activation and Protects Cells from Apoptosis* , 2001, The Journal of Biological Chemistry.

[35]  J. Richardson,et al.  The penultimate rotamer library , 2000, Proteins.

[36]  R. Srinivasan,et al.  Rules for alpha-helix termination by glycine. , 1994, Science.

[37]  A. Whale,et al.  Signalling to cancer cell invasion through PAK family kinases. , 2011, Frontiers in bioscience.