SNJ-1656 / Senju, Novartis - LARVOL DELTA

Thrombospondin 1 Mediates Autophagy Upon Inhibition of the Rho-Associated Protein Kinase Inhibitor. (PubMed, Cells) - "The highly selective and potent ROCK inhibitor Y-39983 enhanced the expression of autophagy genes in ARPE-19 cells and increased autophagic vacuole formation...Our data showed that ROCK inhibitor-induced autophagy was mediated by THBS1 downregulation. We identified ROCK and THBS1 as potential novel therapeutic targets in AMD."

Journal • Age-related Macular Degeneration • CNS Disorders • Macular Degeneration • Ophthalmology • Retinal Disorders

EXPLORING ROCK1 INHIBITION IN SILICO: IMPLICATIONS FOR ISCHEMIC STROKE TREATMENT OPTIMIZATION (WSC 2024) - "Three-dimensional structures of eight ligands/inhibitors (fasudil, dimethyl-fasudil, ripasudil, hydroxy-fasudil, FSD-C10, SNJ-1656, SAR407899, and Y27632) were generated using Marvinsketch and converted to PDB format. Conclusions Inhibitors with high binding affinity could hinder substrate entry to the ROCK1 active site, decreasing its activity. Assessing the selectivity of ROCK inhibitors (in silico) towards ROCK1 may serve as a predictive tool for evaluating therapeutic efficacy and potential adverse effects before conducting in vitro studies."

Cardiovascular • CNS Disorders • Ischemic stroke • Vascular Neurology • ROCK1

E3 ubiquitin ligase UBR5 promotes gemcitabine resistance in pancreatic cancer by inducing O-GlcNAcylation-mediated EMT via destabilization of OGA. (PubMed, Cell Death Dis) - "Pancreatic cancer (PC) is among the deadliest malignancies, with an extremely poor diagnosis and prognosis. The combination of Y-39983 dihydrochloride and GEM attenuated tumour growth in a mouse xenograft tumour model. Collectively, these data demonstrated that UBR5 plays a pivotal role in the sensitisation of PC to GEM and provides a potential therapeutic strategy to overcome GEM resistance."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • Targeted Protein Degradation • UBR5

ROCK inhibitor upregulates autophagy gene expressions and autophagy flux in human ARPE-19 (ARVO 2024) - "Our findings suggest that Y39983 does not affect ARPE-19 cell viability, indicating the absence of toxicity. Y39983 is found to alter ARPE-19 intracellular cell architecture. Our results also suggest that ROCK inhibitor Y-39983 enhanced autophagy of ARPE-19 cells at the gene level and increased the autophagy flux."

Age-related Macular Degeneration • Macular Degeneration • Ophthalmology • Retinal Disorders • ATG5 • ATG7 • TFEB

Mass production of iPSC-derived platelets toward the clinical application. (PubMed, Regen Ther) - "We also optimized a culture cocktail for maturation of the imMKCLs by mixing an aryl hydrocarbon receptor (AhR) antagonist, SR1/GNF-316; a Rho-associated protein kinase (ROCK) inhibitor, Y-27632/Y-39983; and a small-molecule compound replacing recombinant thrombopoietin (TPO), TA-316...Combination of the MCB and VerMES enabled us to produce more than 100 billion iPSC-PLTs, leading to the first-in-human clinical trial. Despite these advancements, many challenges remain before expanding the clinical implementation of this strategy."

Journal • Review • BCL2L1 • BMI1 • MYC

ROCK Inhibitors as an Alternative Therapy for Corneal Grafting: A Systematic Review. (PubMed, J Ocul Pharmacol Ther) - "The systematic review was done from PubMed, Scopus, Web of Science, and Google Scholar for CWH, corneal injury, corneal endothelial wound healing, ROCK inhibitors, Fasudil, Netarsudil, Ripasudil, Y-27632, clinical trial, clinical study, case series, case reports, preclinical study, in vivo, and in vitro studies. ROCK inhibitors were effective topical treatments for corneal infections. Ripasudil, Y-27632, H-1152, Y-39983, and AMA0526 are a few new ROCK inhibitors that may help CWH and replace human donor tissue."

Journal • Review • Cardiovascular • Cataract • Corneal Abrasion • Fibrosis • Glaucoma • Infectious Disease • Ophthalmology • Transplantation

Identifying new drugs and targets to treat rapidly elevated intraocular pressure for angle closure and secondary glaucomas to curb visual impairment. (PubMed, Exp Eye Res) - "However, translation of the novel animal-based findings to the human conditions remains to be demonstrated but represent viable targets, especially EP-receptor agonists (e.g. omidenepag isopropyl; AL-6598; butaprost), mixed activity serotonin/dopamine receptor agonists (e.g. cabergoline), rho kinase inhibitors (e.g. AMA0076, Y39983), CACNA2D1-gene product inhibitors (e.g. pregabalin), melatonin receptor agonists, and certain K-channel openers (e.g. nicorandil, pinacidil). Other drug candidates and targets were also identified and will be discussed."

Journal • Review • Cardiovascular • Glaucoma • Infectious Disease • Ocular Inflammation • Ophthalmology

EVALUTAION OF VARIOUS RHO-ASSOCIATED KINASE (ROCK) INHIBITORS ON THE ATTACHMENT AND PROLIFERATION OF PRIMARY CORNEAL ENDOTHELIAL CELLS (ARVO 2022) - "Both classes of Aminofurazan and Benzodiazapiene ROCKi had a negative impact on HCEnCs at 30mM, whereas the Y-39983 molecule were detrimental to the HCEnCs from 10mM. We were able to demonstrate that various ROCKi evaluated including Ripasudil (K-115) and Netarsudil (AR-13324 and AR-13503) were comparable in their capacity to improve cellular attachment of HCEnCs at various concentrations. Subsequent evaluation revealed the Netarsudil molecules to aid proliferation of HCEnCs even when used at lower concentrations to Y-27632. Further functional assessment of Netarsudil within a cell injection rabbit model of bullous keratopathy is currently on going."

Ophthalmology

High-Throughput NanoBiT-Based Screening for Inhibitors of HIV-1 Vpu and Host BST-2 Protein Interaction. (PubMed, Int J Mol Sci) - "Furthermore, the Vpu-mediated enhancement of pesudotyped viral particle production was inhibited by Y-39983 HCl. Our findings indicate that our newly developed assay can be used for the discovery of potential antiviral molecules with novel mechanisms of action."

Journal • Human Immunodeficiency Virus • Immunology • Infectious Disease • BST2

Thrombospondin-1 mediates Rho-kinase inhibitor-induced increase in outflow-facility. (PubMed, J Cell Physiol) - "Likewise, LSKL triggered a dose-dependent increase in outflow facility in ex vivo mouse eyes, to a similar extent as Y39983 (83.8% increase by Y39983 vs. 71.2% increase by LSKL at 50 µM). There were no additive effects with simultaneous treatment with LSKL and Y39983, supporting the notion that the effects of ROCK inhibition were mediated by TSP1."

Journal • Glaucoma • Ophthalmology

[VIRTUAL] The Role of Thrombospondin-1 in Rho-kinase Inhibitor Mediated Changes in Outflow Facility (ARVO 2021) - "Y39983 down-regulated the TSP-1 expression in hTM and silencing TSP-1 gene expression improved the outflow facility. Since there was no additive effect with combined treatment of Y39983 and TSP-1 blockade, the results suggests that TSP-1 is a downstream effector of ROCK inhibition that regulates outflow facility."

Glaucoma • Ophthalmology

Rho-kinase (ROCK) Inhibitors- A Neuroprotective Therapeutic Paradigm with a Focus on Ocular Utility. (PubMed, Curr Med Chem) - "Based on the results of high-throughput screening, several Rho kinase inhibitors have been designed and developed comprising of diverse scaffolds exhibiting Rho kinase inhibitory activity from micromolar to subnanomolar ranges. This diversity in the scaffolds with inhibitory potential against the kinase and their SAR development will be intricated in the present review. Ripasudil is the only Rho kinase inhibitor marketed to date for the treatment of glaucoma. Another ROCK inhibitor AR-13324 has recently passed the clinical trials whereas AMA0076, K115, PG324, Y39983 and RKI-983 are still under trials. In view of this, a detailed and updated account of ROCK II inhibitors as the next generation therapeutic agents for glaucoma will be discussed in this review."

Journal • Alzheimer's Disease • Cardiovascular • CNS Disorders • Complement-mediated Rare Disorders • Gene Therapies • Glaucoma • Hypertension • Ischemic stroke • Multiple Sclerosis • Myocardial Ischemia • Nephrology • Ocular Inflammation • Ophthalmology • Optic Neuritis • Orthopedics • Pain • Renal Disease • Reperfusion Injury

The effects of a Rho-associated protein kinase (ROCK) inhibitor (Y39983) on human trabecular meshwork cells – a morphological and proteomic study (ARVO 2019) - "Upregulation of TSP1 has previously been reported in corticosteroid-treated TM cells. The downregulation of TSP1 after Y39983 treatment suggests it may be potential target for understanding the mechanistic action of ROCK inhibitors on TM cells."