Substituted 2H-isoquinolin-1-ones as potent Rho-kinase inhibitors: Part 3, aryl substituted pyrrolidines

Bosanac, Todd; Hickey, Eugene R.; Ginn, John D.; Kashem, Mohammed A.; Kerr, Steven; Kugler, Stanley; Li, Xiang; Olague, Alan; Schlyer, Sabine; Young, Erick R.R.

doi:10.1016/j.bmcl.2010.04.069

Cited by 38 publications

(23 citation statements)

References 19 publications

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“…Shaded boxes illustrate where molecules are different from the reference GSK180736A or GSK2163632A compounds. (d) ROCK inhibitors CHEMBL225282 30 and CHEMBL1082820, 31 related to the indazole class. (e) IGF-1R inhibitors CHEMBL464552 51 and CHEMBL507625, 27 related to the pyrrolopyrimidine class.…”

Section: Results and Discussionmentioning

confidence: 99%

“…There is a high level of sequence conservation within the GRK2 and ROCK1 active sites, as both are members of the AGC kinase family and contain nearly identical residues at signature positions. 29 Comparison with cocrystal structures of the indazole derivatives, including that of CHEMBL225282 (PDB entry 3V8S), 30 and of the isoquinoline derivatives, CHEMBL1222571 (3NCZ) 25 and CHEMBL1082820 (3NDM) 31 (Figure 1 d), in complex with ROCK1 reveal that they form analogous interactions with the hinge of the kinase domain. Their terminal phenyl groups all interact with the P-loop in an analogous way to that of GSK180736A (Figures 3 b and 4 a).…”

Section: Results and Discussionmentioning

confidence: 99%

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Identification and Structure–Function Analysis of Subfamily Selective G Protein-Coupled Receptor Kinase Inhibitors

et al. 2014

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Selective inhibitors of individual subfamilies of G protein-coupled receptor kinases (GRKs) would serve as useful chemical probes as well as leads for therapeutic applications ranging from heart failure to Parkinson’s disease. To identify such inhibitors, differential scanning fluorimetry was used to screen a collection of known protein kinase inhibitors that could increase the melting points of the two most ubiquitously expressed GRKs: GRK2 and GRK5. Enzymatic assays on 14 of the most stabilizing hits revealed that three exhibit nanomolar potency of inhibition for individual GRKs, some of which exhibiting orders of magnitude selectivity. Most of the identified compounds can be clustered into two chemical classes: indazole/dihydropyrimidine-containing compounds that are selective for GRK2 and pyrrolopyrimidine-containing compounds that potently inhibit GRK1 and GRK5 but with more modest selectivity. The two most potent inhibitors representing each class, GSK180736A and GSK2163632A, were cocrystallized with GRK2 and GRK1, and their atomic structures were determined to 2.6 and 1.85 Å spacings, respectively. GSK180736A, developed as a Rho-associated, coiled-coil-containing protein kinase inhibitor, binds to GRK2 in a manner analogous to that of paroxetine, whereas GSK2163632A, developed as an insulin-like growth factor 1 receptor inhibitor, occupies a novel region of the GRK active site cleft that could likely be exploited to achieve more selectivity. However, neither compound inhibits GRKs more potently than their initial targets. This data provides the foundation for future efforts to rationally design even more potent and selective GRK inhibitors.

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Section: Results and Discussionmentioning

confidence: 99%

Section: Results and Discussionmentioning

confidence: 99%

Identification and Structure–Function Analysis of Subfamily Selective G Protein-Coupled Receptor Kinase Inhibitors

et al. 2014

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“…To this end, both traditional high‐throughput library screens and fragment‐based drug discovery efforts have yielded compounds that are reported to have significant selectivity for ROCK2 relative to ROCK1 [46,47,48]. Structural solutions of ROCK1 complexes with inhibitors such as Y27632, fasudil, hydroxyfasudil and H‐1152P provide a significant amount of structure–activity relationship data for improving potency and selectivity [28,46,49,50]. The next advance in determining whether the hypothesis that targeting ROCK2 would be adequate for cancer treatment, and superior to pan‐ROCK inhibition for limiting adverse effects, will come from in vivo studies using compounds with ROCK2 selectivity and from conditional tissue‐selective ROCK2 knockout experiments in genetically modified mouse cancer models.…”

Section: Rock Features and Regulationmentioning

confidence: 99%

Rho‐associated kinases in tumorigenesis: re‐considering ROCK inhibition for cancer therapy

2012

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The Rho-associated (ROCK) serine/threonine kinases have emerged as central regulators of the actomyosin cytoskeleton, their main purpose being to promote contractile force generation. Aided by the discovery of effective inhibitors such as Y27632, their roles in cancer have been extensively explored with particular attention focused on motility, invasion and metastasis. Recent studies have revealed a surprisingly diverse range of functions of ROCK. These insights could change the way ROCK inhibitors might be used in cancer therapy to include the targeting of stromal rather than tumour cells, the concomitant blocking of ROCK and proteasome activity in K-Ras-driven lung cancers and the combination of ROCK with tyrosine kinase inhibitors for treating haematological malignancies such as chronic myeloid leukaemia. Despite initial optimism for therapeutic efficacy of ROCK inhibition for cancer treatment, no compounds have progressed into standard therapy so far. However, by carefully defining the key cancer types and expanding the appreciation of ROCK's role in cancer beyond being a cell-autonomous promoter of tumour cell invasion and metastasis, the early promise of ROCK inhibitors for cancer therapy might still be realized. Keywords: ROCK; actin; cytoskeleton; inhibitor; cancer EMBO reports (2012) 13, 900-908; published online 11 September 2012; doi:10.1038/embor.2012 See the Glossary for abbreviations used in this article. IntroductionThe Rho GTPase family is best known for its well-characterized roles in regulation of actin cytoskeleton organization and dynamics [1]. The actions of Rho proteins are mediated by effector proteins, which might have intrinsic catalytic activity, act as scaffolds for protein complexes and in some instances serve both functions [2]. The RhoA and RhoC family members act primarily to promote actomyosin contractile force generation through ROCK1-and ROCK2-mediated phosphorylation of numerous downstream target proteins, including LIM kinases 1 and 2 (LIMK1 and LIMK2), the myosin regulatory light chain (MLC), and the myosin binding subunit (MYPT1) of the MLC phosphatase to inhibit catalytic activity and consequent MLC dephosphorylation (Fig 1; [3,4]). Collectively, these events promote actin filament stabilization through LIMKmediated phosphorylation and inactivation of cofilin family proteins, and through MLC phosphorylation leading to increased actin filament bundling and myosin-driven contraction. The increase in actomyosin contractility contributes directly to several proximal processes, such as regulation of morphology, motility, and cell-cell and cell-matrix adhesion. In addition, ROCK kinases influence more distal cellular processes including gene transcription, proliferation, differentiation, apoptosis and oncogenic transformation, although in many instances the molecular mechanisms have not been fully characterized. Given the wide spectrum of biological processes influenced by ROCK, it is not surprising that they have been implicated in numerous aspects of cancer. Reinforcing this a...

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“…Due to potential therapeutic applications, significant research efforts have been directed towards the identification of more potent and more selective ROCK inhibitors, 38–43 including isoquinolinamines 44,45 triazines, 46 isoquinolinones, 47,48 quinazolinones, 49 benzothiazoles 50 and diaminopyrazines 51 and their use for the treatment of cardiovascular diseases and CNS disorders. To the best of our knowledge the antitumor and antimetastatic properties of these inhibitors has yet to be shown or published.…”

Section: Introductionmentioning

confidence: 99%

Pyridylthiazole-based ureas as inhibitors of Rho associated protein kinases (ROCK1 and 2)

et al. 2012

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Potent ROCK inhibitors of a new class of 1-benzyl-3-(4-pyridylthiazol-2-yl)ureas have been identified. Remarkable differences in activity were observed for ureas bearing a benzylic stereogenic center. Derivatives with hydroxy, methoxy and amino groups at the meta position of the phenyl ring give rise to the most potent inhibitors (low nM). Substitutions at the para position result in substantial loss of potency. Changes at the benzylic position are tolerated resulting in significant potency in the case of methyl and methylenehydroxy groups. X-Ray crystallography was used to establish the binding mode of this class of inhibitors and provides an explanation for the observed differences of the enantiomer series. Potent inhibition of ROCK in human lung cancer cells was shown by suppression of the levels of phosphorylation of the ROCK substrate MYPT-1.

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Substituted 2H-isoquinolin-1-ones as potent Rho-kinase inhibitors: Part 3, aryl substituted pyrrolidines

Cited by 38 publications

References 19 publications

Identification and Structure–Function Analysis of Subfamily Selective G Protein-Coupled Receptor Kinase Inhibitors

Identification and Structure–Function Analysis of Subfamily Selective G Protein-Coupled Receptor Kinase Inhibitors

Rho‐associated kinases in tumorigenesis: re‐considering ROCK inhibition for cancer therapy

Pyridylthiazole-based ureas as inhibitors of Rho associated protein kinases (ROCK1 and 2)

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