A Novel Approach to Treating Multiple Diseases by Small Molecule Targeting of G-Proteins - One Step Beyond GPCRs

Brief Description
Despite the prevalence of GPCR targeting as a therapeutic paradigm, there are few approved or in-development therapeutics targeting the downstream effectors to which GPCRs are coupled (i.e., the G-proteins alpha and ßgamma).  Both Galpha and Gßgamma act as the downstream messengers of activated receptors and elicit specific biological responses.  Targeting the G-proteins' messengers could present a tremendous therapeutic advantage by offering greater efficacy and enhancement of selectivity not possible by targeting the receptor itself.  Of greatest interest and therapeutic potential are small molecules which disrupt the ability of Gßgamma to activate subsequent effectors in a particular GPCR-mediated signaling pathway.  As such, small molecule inhibition of Gßgamma represents a significant means for the treatment of a number of GPCR-related pathological conditions, including:

Heart Failure and HypertensionßARK1ct prevents overload hypertrophy
Inflammation:  Gßgamma plays a critical role in leukocyte migration in response to chemoattractants
Pain:  Gßgamma-dependent regulation of PLC may inhibit opioid signaling, blockade of this pathway could increase the potency of µ-opioid receptor agonists

A platform for Gßgamma-targeted drug discovery has been developed by investigators at the University of Rochester Medical Center.  The technology permits rapid in silico  and in vitro screening of small molecule libraries to identify compounds which selectively bind and functionally inhibit Gßgamma.  The methods are both sensitive and flexible, having already led to the identification of multiple high-affinity compounds which can block distinct Gßgamma functions, including in vito  protein-protein interactions and related biological signaling responses in intact cells and animal models.  This platform technology can serve as an expansive drug discovery engine, potentially yielding proprietary therapeutics with novel mechanisms of action.  The platform has thus far produced discoveries in three specific areas of clinical interest:

Heart Failure and Hypertension: (>$60 BB Market): Drs. Srmcka and Burns Blaxall at the University of Rochester have identified compounds which block an interaction between Gßgamma and one of its downstream effectors, ßARK1, involved in the regulation of cardiac function. The disruption of this interaction prevents the subsequent activation of ßARK1, which has been shown to be therapeutically useful for treating and reversing congestive heart failure. Most importantly, this compound functions in vitro similar to ßARK1ct (see note above on ßARK1ct) and appears to be bioavailable and cell permeable.  Preliminary data indicate that this compound increases cardiomyocyte contractility at baseline and in response to ß-adrenergic receptor agonists.  Dramatic normalization of cardiac function and morphology are observed in an animal model of heart failure. Beyond heart failure, inhibition of the Gßgamma-ßARK1 interaction via ßARK1ct gene therapy has proven effective in the treatment of hypertension and vascular restenosis, suggesting broad cardiovascular benefits for the new compound.
Inflammation:  (>$10 BB Market):  Dr. Alan Smrcka at the University of Rochester has identified compounds that block key inflammatory signal transduction processes.  One compound blocks fMLP-mediated PI3 kinase activation and fMLP-dependent neutrophil (HL60 cell) chemotaxis-processes dependent on Gßγ function.  In a mouse footpad carrageena-induced inflammation model, administration of this compound dramatically reduced markers of inflammatory response with an observed efficacy comparable to indomethacin.
Pain: (>$23 BB market): Studies by Drs. Srmcka and Jean Bidlack at the University of Rochester have shown that one newly identified compound enhances µ-opioid receptor-dependent anti-nociception, blocks development of opioid tolerance, and prevents opiate withdrawal when co-administered with morphine.

Small molecule inhibition of specific aspects of Gßγ-dependent signaling offers a powerful and yet-to-be exploited therapeutic strategy with multiple applications and advantages:

Heart Failure: A small molecule inhibitor of ßARK1 activation will have significantly better bioavailability, delivery, and safety advantages versus the ßARK1ct gene therapy approach.  The small molecule inhibitor could also be indicated for the treatment of both chronic and acute heart failure, depending on formulation and dosing.  The therapeutic could also be used in conjunction with implanted devices such as left ventricular assist devices.
Inflammation: Higher specificity therapeutics for the treatment of inflammatory diseases could be developed which avoid the non-specific effects of previous generation anti-inflammatory agents.
Pain: A new class of combination therapeutics may be developed where the effective dose of opiates can be reduced and problems of dependence and tolerance are avoided.

This therapeutic approach has been validated by Genzyme who have sponsored clinical trials to evaluate a gene therapy approach for delivering ßARK1ct as a treatment for heart failure.
Patent Information:
Title Country Patent No. Issued Date
Compositions and Methods for Inhibiting G Protein Signaling United States 8,975,259 3/10/2015
For Information, Contact:
Matan Rapoport
Licensing Associate
University of Rochester
Alan Smrcka
Burns Blaxall
Jean Bidlack
Small Molecule