title: A novel selective multikinase inhibitor of ROCK and MRCK effectively blocks cancer cell migration and invasion.
abstract: Two structurally related protein kinase families, the Rho kinases (ROCK) and the myotonic dystrophy kinase-related Cdc42-binding kinases (MRCK) are required for migration and invasion of cancer cells. We hypothesized that simultaneous targeting of these two kinase families might represent a novel therapeutic strategy to block the migration and invasion of metastatic cancers. To this end, we developed DJ4 as a novel small molecule inhibitor of these kinases. DJ4 potently inhibited activities of ROCK and MRCK in an ATP competitive manner. In cellular functional assays, DJ4 treatment significantly blocked stress fiber formation and inhibited migration and invasion of multiple cancer cell lines in a concentration dependent manner. Our results strongly indicate that DJ4 may be further developed as a novel anti-metastatic chemotherapeutic agent for multiple cancers.
authors.affiliation: Department of Pharmacology, Penn State Hershey College of Medicine, Hershey, PA 17033, USA.
authors.forename: Vijay Pralhad
authors.initials: VP
authors.lastname: Kale
authors.affiliation: Department of Pharmacology, Penn State Hershey College of Medicine, Hershey, PA 17033, USA.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Hengst
authors.affiliation: Department of Pharmacology, Penn State Hershey College of Medicine, Hershey, PA 17033, USA.
authors.forename: Dhimant H
authors.initials: DH
authors.lastname: Desai
authors.affiliation: Department of Pharmacology, Penn State Hershey College of Medicine, Hershey, PA 17033, USA.
authors.forename: Taryn E
authors.initials: TE
authors.lastname: Dick
authors.affiliation: Department of Pharmacology, Penn State Hershey College of Medicine, Hershey, PA 17033, USA.
authors.forename: Katherine N
authors.initials: KN
authors.lastname: Choe
authors.affiliation: Department of Pharmacology, Penn State Hershey College of Medicine, Hershey, PA 17033, USA.
authors.forename: Ashley L
authors.initials: AL
authors.lastname: Colledge
authors.affiliation: Department of Pharmacology, Penn State Hershey College of Medicine, Hershey, PA 17033, USA.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Pharmacology, Penn State Hershey College of Medicine, Hershey, PA 17033, USA.
authors.forename: Shen-Shu
authors.initials: SS
authors.lastname: Sung
authors.affiliation: Department of Pharmacology, Penn State Hershey College of Medicine, Hershey, PA 17033, USA.
authors.forename: Shantu G
authors.initials: SG
authors.lastname: Amin
authors.affiliation: Department of Pharmacology, Penn State Hershey College of Medicine, Hershey, PA 17033, USA. Electronic address: jky1@psu.edu.
authors.forename: Jong K
authors.initials: JK
authors.lastname: Yun
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D006801:Humans; D065636:Myotonin-Protein Kinase / Q000037:antagonists & inhibitors*; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D053778:Thiazolidines / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: C000595969:2-5-(1H-pyrrolo(2,3-b)pyridine-3-ylmethylene)-1,3-thiazol-4(5H)-one; D047428:Protein Kinase Inhibitors; D053778:Thiazolidines; C105518:CDC42BPA protein, human; C118666:CDC42BPB protein, human; D065636:Myotonin-Protein Kinase; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases
keywords: Cancer; MRCK; Migration; Multikinase inhibitor; ROCK; Stress fibers