Office of Technology Transfer – University of Michigan

Selective Inhibitors of G-Couple Protein Receptor Kinases

Technology #6328

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Researchers
Scott D. Larsen
Managed By
Ed Pagani
Assistant Director, Health Technologies 734-763-3558
Patent Protection
US Patent Pending US-2017-0240538-A1

This year, nearly 800,000 Americans will have a heart attack and ultimately be diagnosed with heart disease. For those who survive, the damaged heart tissue can continue to atrophy over time leading to decreased quality of life as well as increased risk of a heart failure. Therapeutic options for this population leave much to be desired, as most regimens utilize beta blockers that can put stress on other organs and in many cases increase the risk of heart failure. In order to improve outcomes for heart disease patients, we launched an aggressive campaign to understand and modulate the signaling events that occur in myocardial tissue. After solving the structures of several enzymes responsible for the regulation of heart function and implicated in heart failure, we have rationally designed a series of small molecule inhibitors that are excellent drug candidates and in addition would represent a new class of cardiovascular drugs. These inhibitors selectively target the G-protein coupled receptor kinase GRK2, a protein which down regulates signaling through the g-protein coupled receptor pathway.

GRK2 Inhibitors Target the Root Cause of Heart Failure

In order to combat heart disease, the leading cause of death in the United States, it is imperative that new drugs be developed that target faulty signaling pathways with ultra-high specificity. This point is illustrated in the case of GRK2, whose inhibition has been shown to drastically improve cardiovascular outcomes in animal models but has been an inviable drug candidate until now because of its close structural similarity with other kinases. By solving the structures of a large number of GRK’s, we were able to develop a class of molecules that show up to 1000 fold selectivity vs other GRK’s while maintaining nanomolar IC50 values for GRK2. This class of drugs addresses the root cause of heart failure (desensitization of GPCRs responsible for sympathetic control of the heart) by attenuating the natural down regulation mechanism, in contrast to the commonly used beta-blockers which inhibit GPCRs directly. Aggressive pre-clinical work is being pursued with these compounds as they show unprecedented specificity for an elusive drug target.

Applications

  • Drugs for prevention of heart failure for high risk patients
  • Drugs for prevention of heart atrophy following a heart attack

Advantages

  • Unprecedented selectivity
  • Addresses the root cause of heart failure by attenuating the natural down regulation mechanism