A novel selective multikinase inhibitor of ROCK and MRCK effectively blocks cancer cell migration and invasion

Vijay Pralhad Kale, Jeremy Hengst, Dhimant Desai, Taryn E. Dick, Katherine N. Choe, Ashley L. Colledge, Yoshinori Takahashi, Shen-shu Sung, Shantu Amin, Jong Yun

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)299-310
Number of pages12
JournalCancer Letters
Volume354
Issue number2
DOIs
StatePublished - Nov 28 2014

Fingerprint

Myotonic Dystrophy
Cell Movement
Phosphotransferases
Neoplasms
rho-Associated Kinases
Stress Fibers
Protein Kinases
Adenosine Triphosphate
Cell Line

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

@article{3bd3edd736bb40bfbf718b22a2cf3c92,
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.",
author = "Kale, {Vijay Pralhad} and Jeremy Hengst and Dhimant Desai and Dick, {Taryn E.} and Choe, {Katherine N.} and Colledge, {Ashley L.} and Yoshinori Takahashi and Shen-shu Sung and Shantu Amin and Jong Yun",
year = "2014",
month = "11",
day = "28",
doi = "10.1016/j.canlet.2014.08.032",
language = "English (US)",
volume = "354",
pages = "299--310",
journal = "Cancer Letters",
issn = "0304-3835",
publisher = "Elsevier Ireland Ltd",
number = "2",

}

A novel selective multikinase inhibitor of ROCK and MRCK effectively blocks cancer cell migration and invasion. / Kale, Vijay Pralhad; Hengst, Jeremy; Desai, Dhimant; Dick, Taryn E.; Choe, Katherine N.; Colledge, Ashley L.; Takahashi, Yoshinori; Sung, Shen-shu; Amin, Shantu; Yun, Jong.

In: Cancer Letters, Vol. 354, No. 2, 28.11.2014, p. 299-310.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A novel selective multikinase inhibitor of ROCK and MRCK effectively blocks cancer cell migration and invasion

AU - Kale, Vijay Pralhad

AU - Hengst, Jeremy

AU - Desai, Dhimant

AU - Dick, Taryn E.

AU - Choe, Katherine N.

AU - Colledge, Ashley L.

AU - Takahashi, Yoshinori

AU - Sung, Shen-shu

AU - Amin, Shantu

AU - Yun, Jong

PY - 2014/11/28

Y1 - 2014/11/28

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84908004722&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84908004722&partnerID=8YFLogxK

U2 - 10.1016/j.canlet.2014.08.032

DO - 10.1016/j.canlet.2014.08.032

M3 - Article

C2 - 25172415

AN - SCOPUS:84908004722

VL - 354

SP - 299

EP - 310

JO - Cancer Letters

JF - Cancer Letters

SN - 0304-3835

IS - 2

ER -