Substituted 2H-isoquinolin-1-one as potent Rho-Kinase inhibitors. Part 1: Hit-to-lead account

Wu, Frank; Büttner, Frank; Chen, Rhonda; Hickey, Eugene R.; Jakes, Scott; Kaplita, Paul V.; Kashem, Mohammed A.; Kerr, Steven; Kugler, Stanley; Paw, Zofia; Prokopowicz, Anthony S.; Shih, Cheng-Kon; Snow, Roger J.; Young, Erick R.R.; Cywin, Charles L.

doi:10.1016/j.bmcl.2010.04.070

Cited by 14 publications

(6 citation statements)

References 18 publications

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“…This depletion factor which is only valid for reversible (not for Ibrutinib) ATP competitive inhibition was derived from a pull down of pull down experiment. The obtained kinobead profiles were then compared against known targets of the nine drugs, which were manually compiled from 20 different sources ,,,,− (Supplemental Tables 1–9). We believe that this drug target compilation is of further value as an extensive target catalogue of these nine kinase inhibitors.…”

Section: Resultsmentioning

confidence: 99%

Optimized Chemical Proteomics Assay for Kinase Inhibitor Profiling

et al. 2015

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Solid supported probes have proven to be an efficient tool for chemical proteomics. The kinobeads technology features kinase inhibitors covalently attached to Sepharose for affinity enrichment of kinomes from cell or tissue lysates. This technology, combined with quantitative mass spectrometry, is of particular interest for the profiling of kinase inhibitors. It often leads to the identification of new targets for medicinal chemistry campaigns where it allows a two-in-one binding and selectivity assay. The assay can also uncover resistance mechanisms and molecular sources of toxicity. Here we report on the optimization of the kinobead assay resulting in the combination of five chemical probes and four cell lines to cover half the human kinome in a single assay (∼ 260 kinases). We show the utility and large-scale applicability of the new version of kinobeads by reprofiling the small molecule kinase inhibitors Alvocidib, Crizotinib, Dasatinib, Fasudil, Hydroxyfasudil, Nilotinib, Ibrutinib, Imatinib, and Sunitinib.

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Section: Resultsmentioning

confidence: 99%

Optimized Chemical Proteomics Assay for Kinase Inhibitor Profiling

et al. 2015

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“…Compared with compound 11, compound 12 showed significantly improved ROCK2 inhibitory activity (IC 50 = 12 nM). 115 Moreover, the kinase Prkcl2 showed moderate inhibitory activity (IC 50 = 110 nM). To increase compound exposure, the key was to eliminate the metabolically unstable phenyl glycine.…”

Section: Rock Inhibitorsmentioning

confidence: 99%

Application and Study of ROCK Inhibitors in Pulmonary Fibrosis: Recent Developments and Future Perspectives

et al. 2023

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Rho-associated coiled-coil-containing kinases (ROCKs), serine/threonine protein kinases, were initially identified as downstream targets of the small GTP-binding protein Rho. Pulmonary fibrosis (PF) is a lethal disease with limited therapeutic options and a particularly poor prognosis. Interestingly, ROCK activation has been demonstrated in PF patients and in animal PF models, making it a promising target for PF treatment. Many ROCK inhibitors have been discovered, and four of these have been approved for clinical use; however, no ROCK inhibitors are approved for the treatment of PF patients. In this article, we describe ROCK signaling pathways and the structure–activity relationship, potency, selectivity, binding modes, pharmacokinetics (PKs), biological functions, and recently reported inhibitors of ROCKs in the context of PF. We will also focus our attention on the challenges to be addressed when targeting ROCKs and discuss the strategy of ROCK inhibitor use in the treatment of PF.

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“…Despite the satisfactory potential, this compound suffered from limitations such as poor oral bioavailability and poor in vitro microsomal stability. 292 The scaffold identified was further subjected to structural optimization for dual ROCK1/ROCK2 inhibition, and N-dealkylated analogue 139, with improved microsomal stability and intact potency, was discovered. Despite this optimistic and promising activity profile, a dramatic loss in potency in an aortic ring relaxation assay was observed.…”

Section: Recent Medicinal Chemistry Campaigns For Ocular Drug Discove...mentioning

confidence: 99%

“…Attempts to discover potent ROCK inhibitors led to the identification of the potent isoquinoline-based compound 138 . Despite the satisfactory potential, this compound suffered from limitations such as poor oral bioavailability and poor in vitro microsomal stability . The scaffold identified was further subjected to structural optimization for dual ROCK1/ROCK2 inhibition, and N -dealkylated analogue 139 , with improved microsomal stability and intact potency, was discovered.…”

Section: Recent Medicinal Chemistry Campaigns For Ocular Drug Discove...mentioning

confidence: 99%

Ocular Disease Therapeutics: Design and Delivery of Drugs for Diseases of the Eye

et al. 2020

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The ocular drug discovery field has evidenced significant advancement in the past decade. The FDA approvals of Rhopressa, Vyzulta, and Roclatan for glaucoma, Brolucizumab for wet age-related macular degeneration (wet AMD), Luxturna for retinitis pigmentosa, Dextenza (0.4 mg dexamethasone intracanalicular insert) for ocular inflammation, ReSure sealant to seal corneal incisions, and Lifitegrast for dry eye represent some of the major developments in the field of ocular therapeutics. A literature survey also indicates that gene therapy, stem cell therapy, and target discovery through genomic research represent significant promise as potential strategies to achieve tissue repair or regeneration and to attain therapeutic benefits in ocular diseases. Overall, the emergence of new technologies coupled with first-in-class entries in ophthalmology are highly anticipated to restructure and boost the future trends in the field of ophthalmic drug discovery. This perspective focuses on various aspects of ocular drug discovery and the recent advances therein. Recent medicinal chemistry campaigns along with a brief overview of the structure–activity relationships of the diverse chemical classes and developments in ocular drug delivery (ODD) are presented.

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Substituted 2H-isoquinolin-1-one as potent Rho-Kinase inhibitors. Part 1: Hit-to-lead account

Cited by 14 publications

References 18 publications

Optimized Chemical Proteomics Assay for Kinase Inhibitor Profiling

Optimized Chemical Proteomics Assay for Kinase Inhibitor Profiling

Application and Study of ROCK Inhibitors in Pulmonary Fibrosis: Recent Developments and Future Perspectives

Ocular Disease Therapeutics: Design and Delivery of Drugs for Diseases of the Eye

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