title: Development of p21 activated kinase-targeted multikinase inhibitors that inhibit thyroid cancer cell migration.
abstract: BACKGROUND
  The p21 activated kinases (PAKs) are a family of serine/threonine kinases that are downstream effectors of small GTPase Cdc42 and Rac. PAKs regulate cell motility, proliferation, and cytoskeletal rearrangement. PAK isoform expression and activity have been shown to be enhanced in cancer and to function as an oncogene in vivo. PAKs also have been implicated in cancer progression.
  
  
  OBJECTIVE
  In thyroid cancer, we have previously determined that PAK overactivation is common in the invasive fronts of aggressive tumors and that it is functionally involved in thyroid cancer cell motility using molecular inhibitors. We report the development of two new PAK-inhibiting compounds that were modified from the structure OSU-03012, a previously identified multikinase inhibitor that competitively blocks ATP binding of both phosphoinositide-dependent kinase 1 (PDK1) and PAK1.
  
  
  RESULTS
  Seventeen compounds were created by combinatorial chemistry predicted to inhibit PAK activity with reduced anti-PDK1 effect. Two lead compounds were identified based on the ability to inhibit PAK1 activity in an ATP-competitive manner without discernible in vivo PDK1 inhibitory activity in thyroid cancer cell lines. Both compounds reduced thyroid cancer cell viability. Although they are not PAK-specific on a multikinase screening assay, the antimigration activity effect of the compounds in thyroid cancer cells was rescued by overexpression of a constitutively active PAK1, suggesting this activity is involved in this biological effect.
  
  
  CONCLUSIONS
  We have developed 2 new multikinase inhibitors with anti-PAK activity that may serve as scaffolds for further compound development targeting this progression-related thyroid cancer target.
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, Ohio 43210, USA.
authors.forename: Yihui
authors.initials: Y
authors.lastname: Ma
authors.forename: Samantha K
authors.initials: SK
authors.lastname: McCarty
authors.forename: Naval P
authors.initials: NP
authors.lastname: Kapuriya
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Brendel
authors.forename: Chaojie
authors.initials: C
authors.lastname: Wang
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.forename: David
authors.initials: D
authors.lastname: Jarjoura
authors.forename: Motoyasu
authors.initials: M
authors.lastname: Saji
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Ringel
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology*; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors*
chemical_list: C500894:OSU 03012; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578562:PDPK1 protein, human; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases