Fragment-based and structure-guided discovery and optimization of Rho kinase inhibitors

Rongshi Li; Mathew P. Martin; Yan Liu; Binglin Wang; Ronil A. Patel; Jin Yi Zhu; Nan Sun; Roberta Pireddu; Nicholas J. Lawrence; Jiannong Li; Eric B. Haura; Shen Shu Sung; Wayne C. Guida; Ernst Schonbrunn; Said M. Sebti

doi:10.1021/jm201289r

Fragment-based and structure-guided discovery and optimization of Rho kinase inhibitors

Rongshi Li, Mathew P. Martin, Yan Liu, Binglin Wang, Ronil A. Patel, Jin Yi Zhu, Nan Sun, Roberta Pireddu, Nicholas J. Lawrence, Jiannong Li, Eric B. Haura, Shen Shu Sung, Wayne C. Guida, Ernst Schonbrunn, Said M. Sebti

Research output: Contribution to journal › Article › peer-review

44 Scopus citations

Abstract

Using high concentration biochemical assays and fragment-based screening assisted by structure-guided design, we discovered a novel class of Rho-kinase inhibitors. Compound 18 was equipotent for ROCK1 (IC ₅₀ = 650 nM) and ROCK2 (IC ₅₀ = 670 nM), whereas compound 24 was more selective for ROCK2 (IC ₅₀ = 100 nM) over ROCK1 (IC ₅₀ = 1690 nM). The crystal structure of the compound 18-ROCK1 complex revealed that 18 is a type 1 inhibitor that binds the hinge region in the ATP binding site. Compounds 18 and 24 inhibited potently the phosphorylation of the ROCK substrate MLC2 in intact human breast cancer cells.

Original language	English (US)
Pages (from-to)	2474-2478
Number of pages	5
Journal	Journal of Medicinal Chemistry
Volume	55
Issue number	5
DOIs	https://doi.org/10.1021/jm201289r
State	Published - Mar 8 2012
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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title = "Fragment-based and structure-guided discovery and optimization of Rho kinase inhibitors",

abstract = "Using high concentration biochemical assays and fragment-based screening assisted by structure-guided design, we discovered a novel class of Rho-kinase inhibitors. Compound 18 was equipotent for ROCK1 (IC 50 = 650 nM) and ROCK2 (IC 50 = 670 nM), whereas compound 24 was more selective for ROCK2 (IC 50 = 100 nM) over ROCK1 (IC 50 = 1690 nM). The crystal structure of the compound 18-ROCK1 complex revealed that 18 is a type 1 inhibitor that binds the hinge region in the ATP binding site. Compounds 18 and 24 inhibited potently the phosphorylation of the ROCK substrate MLC2 in intact human breast cancer cells.",

author = "Rongshi Li and Martin, {Mathew P.} and Yan Liu and Binglin Wang and Patel, {Ronil A.} and Zhu, {Jin Yi} and Nan Sun and Roberta Pireddu and Lawrence, {Nicholas J.} and Jiannong Li and Haura, {Eric B.} and Sung, {Shen Shu} and Guida, {Wayne C.} and Ernst Schonbrunn and Sebti, {Said M.}",

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doi = "10.1021/jm201289r",

language = "English (US)",

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TY - JOUR

T1 - Fragment-based and structure-guided discovery and optimization of Rho kinase inhibitors

AU - Li, Rongshi

AU - Martin, Mathew P.

AU - Liu, Yan

AU - Wang, Binglin

AU - Patel, Ronil A.

AU - Zhu, Jin Yi

AU - Sun, Nan

AU - Pireddu, Roberta

AU - Lawrence, Nicholas J.

AU - Li, Jiannong

AU - Haura, Eric B.

AU - Sung, Shen Shu

AU - Guida, Wayne C.

AU - Schonbrunn, Ernst

AU - Sebti, Said M.

PY - 2012/3/8

Y1 - 2012/3/8

N2 - Using high concentration biochemical assays and fragment-based screening assisted by structure-guided design, we discovered a novel class of Rho-kinase inhibitors. Compound 18 was equipotent for ROCK1 (IC 50 = 650 nM) and ROCK2 (IC 50 = 670 nM), whereas compound 24 was more selective for ROCK2 (IC 50 = 100 nM) over ROCK1 (IC 50 = 1690 nM). The crystal structure of the compound 18-ROCK1 complex revealed that 18 is a type 1 inhibitor that binds the hinge region in the ATP binding site. Compounds 18 and 24 inhibited potently the phosphorylation of the ROCK substrate MLC2 in intact human breast cancer cells.

AB - Using high concentration biochemical assays and fragment-based screening assisted by structure-guided design, we discovered a novel class of Rho-kinase inhibitors. Compound 18 was equipotent for ROCK1 (IC 50 = 650 nM) and ROCK2 (IC 50 = 670 nM), whereas compound 24 was more selective for ROCK2 (IC 50 = 100 nM) over ROCK1 (IC 50 = 1690 nM). The crystal structure of the compound 18-ROCK1 complex revealed that 18 is a type 1 inhibitor that binds the hinge region in the ATP binding site. Compounds 18 and 24 inhibited potently the phosphorylation of the ROCK substrate MLC2 in intact human breast cancer cells.

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JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 5

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Fragment-based and structure-guided discovery and optimization of Rho kinase inhibitors

Abstract

ASJC Scopus subject areas

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