Fragment-Based and Structure-Guided Discovery and Optimization of Rho Kinase Inhibitors

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

doi:10.1021/jm201289r

Cited by 48 publications

(52 citation statements)

References 27 publications

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“…Upon superimposing these inhibitor structures on ROCK1 in complex with an indazole derivative similar to 2 (3V8S) 33 , it is apparent that ROCK1-Phe120 (Leu235 in GRK2) sterically clashes with each of the four characterized inhibitor D-rings. However, ROCK1-Phe120 must be able to adopt a rotamer more similar to that of GRK2-Leu235 because 12h , 12k , and 12r all inhibit ROCK1 with high potency.…”

Section: Resultsmentioning

confidence: 99%

Structure-Based Design of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors Based on Paroxetine

et al. 2017

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G protein-coupled receptors (GPCRs) are central to many physiological processes. Regulation of this superfamily of receptors is controlled by GPCR kinases (GRKs), some of which have been implicated in heart failure. GSK180736A, developed as a Rho-associated coiled-coil kinase 1 (ROCK1) inhibitor, was identified as an inhibitor of GRK2, and co-crystallized in the active site. Guided by its binding pose overlaid with the binding pose of a known potent GRK2 inhibitor, Takeda103A, a library of hybrid inhibitors was developed. This campaign produced several compounds possessing high potency and selectivity for GRK2 over other GRK subfamilies, PKA, and ROCK1. The most selective compound, 12n (CCG-224406), had an IC50 for GRK2 of 130 nM, greater than 700-fold selectivity over other GRK subfamilies, and no detectable inhibition of ROCK1. Four of the new inhibitors were crystallized with GRK2 to give molecular insights into the binding and kinase selectivity of this class of inhibitors.

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Section: Resultsmentioning

confidence: 99%

Structure-Based Design of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors Based on Paroxetine

et al. 2017

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“…A number of ROCK inhibitors have been developed and significant structure-activity relationship data for improving potency and selectivity are available [137,138] . ROCK inhibitors are currently in several clinical trials, although only AT13148 is developed for cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

Approaches of targeting Rho GTPases in cancer drug discovery

Lin

Zheng

2015

Expert Opinion on Drug Discovery

107

101

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Introduction Rho GTPases are master regulators of actomyosin structure and dynamics and play pivotal roles in a variety of cellular processes including cell morphology, gene transcription, cell cycle progression and cell adhesion. Because aberrant Rho GTPase signaling activities are widely associated with human cancer, key components of Rho GTPase signaling pathways have attracted increasing interest as potential therapeutic targets. Similar to Ras, Rho GTPases themselves were, until recently, deemed “undruggable” because of structure-function considerations. Several approaches to interfere with Rho GTPase signaling have been explored and show promise as new ways for tackling cancer cells. Areas covered This review focuses on the recent progress in targeting the signaling activities of three prototypical Rho GTPases, i.e. RhoA, Rac1, and Cdc42. The authors describe the involvement of these Rho GTPases, their key regulators and effectors in cancer. Furthermore, the authors discuss the current approaches for rationally targeting aberrant Rho GTPases along their signaling cascades, upstream and downstream of Rho GTPases and posttranslational modifications at a molecular level. Expert opinion To date, while no clinically effective drugs targeting Rho GTPase signaling for cancer treatment are available, tool compounds and lead drugs that pharmacologically inhibit Rho GTPase pathways have shown promise. Small molecule inhibitors targeting Rho GTPase signaling may add new treatment options for future precision cancer therapy, particularly in combination with other anti-cancer agents.

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“…Various classic approaches of screening as well as fragment-based drug discovery methods and optimization have led to the identification of compounds with different selectivity for ROCK1 and ROCK2 (Boerma et al, 2008;Ray et al, 2011;Li et al, 2012b). Among them, KD-025 [2-(3-(4-((1H-indazol-5-yl)amino)quinazolin-2-yl) phenoxy)-N-isopropylacetamide; formerly SLx-2119] was the first and remains the only ATP-competitive isoform-selective ROCK2 inhibitor.…”

Section: A Rho-associated Kinase Inhibitorsmentioning

confidence: 99%