Last update 01 Nov 2024

GRK2 x ROCK1

Last update 01 Nov 2024

Basic Info

Related Targets

GRK2ROCK1

Drugs associated with GRK2 x ROCK1

GSK-180736A

Target

GRK2 x ROCK1

Mechanism

GRK2 inhibitors [+1]

Active Org.

GlaxoSmithKline LLC

Originator Org.

GlaxoSmithKline LLC

Active Indication

Heart Failure

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with GRK2 x ROCK1

100 Translational Medicine associated with GRK2 x ROCK1

0 Patents (Medical) associated with GRK2 x ROCK1

Literatures (Medical) associated with GRK2 x ROCK1

01 Apr 2023·Cardiovascular Drugs and TherapyQ3 · MEDICINE

Pepducin ICL1-9-Mediated β2-Adrenergic Receptor-Dependent Cardiomyocyte Contractility Occurs in a Gi Protein/ROCK/PKD-Sensitive Manner

Q3 · MEDICINE

Article

Author: Enjamuri, Nitya ; Tilley, Douglas G ; Carter, Rhonda L ; Lucchese, Anna Maria ; Ibetti, Jessica ; de Lucia, Claudio ; Patwa, Viren ; Cheung, Joseph Y ; Okyere, Ama Dedo ; Koch, Walter J ; Benovic, Jeffrey L ; Song, Jianliang ; Schumacher, Sarah M

PURPOSEβ-Adrenergic receptors (βAR) are essential targets for the treatment of heart failure (HF); however, chronic use of βAR agonists as positive inotropes to increase contractility in a G_s protein-dependent manner is associated with increased mortality. Alternatively, we previously reported that allosteric modulation of β2AR with the pepducin intracellular loop (ICL)1-9 increased cardiomyocyte contractility in a β-arrestin (βarr)-dependent manner, and subsequently showed that ICL1-9 activates the Ras homolog family member A (RhoA). Here, we aimed to elucidate both the proximal and downstream signaling mediators involved in the promotion of cardiomyocyte contractility in response to ICL1-9.METHODSWe measured adult mouse cardiomyocyte contractility in response to ICL1-9 or isoproterenol (ISO, as a positive control) alone or in the presence of inhibitors of various potential components of βarr- or RhoA-dependent signaling. We also assessed the contractile effects of ICL1-9 on cardiomyocytes lacking G protein-coupled receptor (GPCR) kinase 2 (GRK2) or 5 (GRK5).RESULTSConsistent with RhoA activation by ICL1-9, both Rho-associated protein kinase (ROCK) and protein kinase D (PKD) inhibition were able to attenuate ICL1-9-mediated contractility, as was inhibition of myosin light chain kinase (MLCK). While neither GRK2 nor GRK5 deletion impacted ICL1-9-mediated contractility, pertussis toxin attenuated the response, suggesting that ICL1-9 promotes downstream RhoA-dependent signaling in a G_i protein-dependent manner.CONCLUSIONAltogether, our study highlights a novel signaling modality that may offer a new approach to the promotion, or preservation, of cardiac contractility during HF via the allosteric regulation of β2AR to promote G_i protein/βarr-dependent activation of RhoA/ROCK/PKD signaling.

28 Apr 2016·Journal of Medicinal ChemistryQ1 · MEDICINE

Structure-Based Design, Synthesis, and Biological Evaluation of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors

Q1 · MEDICINE

Article

Author: Joseph Y. Cheung ; Kelly M. Larimore ; Osvaldo Cruz-Rodríguez ; Helen V. Waldschmidt ; John J. G. Tesmer ; Walter J. Koch ; Jianliang Song ; Paul D. Kirchhoff ; Marilyn C. Cato ; Jessica Waninger-Saroni ; Alessandro Cannavo ; Scott D. Larsen ; Kristoff T. Homan

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, >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.

16 Jan 2015·ACS Chemical BiologyQ2 · BIOLOGY

Molecular Basis for Small Molecule Inhibition of G Protein-Coupled Receptor Kinases

Q2 · BIOLOGY

Review

Author: Homan, Kristoff T. ; Tesmer, John J. G.

Small molecules that inhibit the protein kinase A, G, and C (AGC) family of serine/threonine kinases can exert profound effects on cell homeostasis and thereby regulate fundamental processes such as heart rate, blood pressure, and metabolism, but there is not yet a clinically approved drug in the United States selective for a member of this family. One subfamily of AGC kinases, the G protein-coupled receptor (GPCR) kinases (GRKs), initiates the desensitization of active GPCRs. Of these, GRK2 has been directly implicated in the progression of heart failure. Thus, there is great interest in the identification of GRK2-specific chemical probes that can be further developed into therapeutics. Herein, we compare crystal structures of small molecule inhibitors in complex with GRK2 to those of highly selective compounds in complex with Rho-associated coiled-coil containing kinase 1 (ROCK1), a closely related AGC kinase. This analysis suggests that reduced hydrogen-bond formation with the hinge of the kinase domain, occupation of the hydrophobic subsite, and, consequently, higher buried surface area are key drivers of potency and selectivity among GRK inhibitors.

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