Reference Detail

Ref Type

Journal Article

PMID

(25840982)

Authors

Sadok A, McCarthy A, Caldwell J, Collins I, Garrett MD, Yeo M, Hooper S, Sahai E, Kuemper S, Mardakheh FK, Marshall CJ

Title

Rho kinase inhibitors block melanoma cell migration and inhibit metastasis.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	75	11	2015 Jun 1	2272-84	Cancer Res

URL

Abstract Text

There is an urgent need to identify new therapeutic opportunities for metastatic melanoma. Fragment-based screening has led to the discovery of orally available, ATP-competitive AKT kinase inhibitors, AT13148 and CCT129254. These compounds also inhibit the Rho-kinases ROCK 1 and ROCK 2 and we show they potently inhibit ROCK activity in melanoma cells in culture and in vivo. Treatment of melanoma cells with CCT129254 or AT13148 dramatically reduces cell invasion, impairing both "amoeboid-like" and mesenchymal-like modes of invasion in culture. Intravital imaging shows that CCT129254 or AT13148 treatment reduces the motility of melanoma cells in vivo. CCT129254 inhibits melanoma metastasis when administered 2 days after orthotopic intradermal injection of the cells, or when treatment starts after metastases have arisen. Mechanistically, our data suggest that inhibition of ROCK reduces the ability of melanoma cells to efficiently colonize the lungs. These results suggest that these novel inhibitors of ROCK may be beneficial in the treatment of metastasis.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
AT13148	AT13148	3	0
CCT129254	CCT129254	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
AT13148		AT-13148\|AT 13148	AKT Inhibitor (Pan) - ATP competitive 7 PKA Inhibitor 2	AT13148 is a small molecule ATP-competitive inhibitor of AGC kinases including AKT1, AKT2, AKT3, p70S6K (RPS6KB1), PKA (PRKACA), ROCK1, ROCK2, RSK1, and SGK3, which results in decreased growth of tumor cells (PMID: 22781553, PMID: 25840982, PMID: 32616501).
CCT129254		AT11854	AKT Inhibitor (Pan) - ATP competitive 7	CCT129254 is a small molecule ATP-competitive inhibitor of AKT and Rho kinases, which results in decreased tumor cell migration and metastasis (PMID: 25840982).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References