Protein Kinase C Epsilon Inhibitors to Treat Pain
Abstract
This is a proposal to develop a new class of drugs to treat pain. These drugs are not opiates and should not be addictive. They are designed to inhibit an enzyme called protein kinase C epsilon (abbreviated PKCe), which we have found over the past 20 years to be important for pain due to inflammation and certain types of nerve damage, for example, resulting from cancer chemotherapy. More recently, we found that repeated stress can cause a generalized increase in sensitivity to pain through a mechanism that also requires PKCe. Our project addresses the Fiscal Year 2017 (FY17) Peer Reviewed Medical Research Program (PRMRP) Topic Area of Non-Opioid Pain Management. It is also applicable to other FY17 PRMRP Topic Areas associated with chronic pain, such as arthritis, chronic migraine and post-traumatic headache, diabetes, Guillain-Barré syndrome, musculoskeletal disorders, rheumatoid arthritis, and scleroderma. The project is divided into four parts. We have recently designed and patented some lead PKCe inhibitors, and we propose here to improve their potency and specificity. We also plan to screen a collection of ~72,000 small molecules to identify new compounds that could be made into a different class of PKCe inhibitors. We will test the most potent compounds that we develop for specificity, drug absorption, metabolism and toxicity and choose the best ones to test in animal models of pain due to inflammation, chemotherapy, or repeated stress. Finally, we will investigate whether these PKCe inhibitors have abuse potential by determining if they are self-administered by rats. We will also test whether they are safe to use together with opiates by testing whether they alter intravenous morphine self-administration by rats. It is our hope that this project will lead to the discovery of at least one PKCe inhibitor that is an effective medication against several types of pain and that has fewer side effects than current pain medications. Pain is an extremely common complaint among military personnel and Veterans. Current pain medications can be effective but carry significant risk of side effects with repeated use. Moreover, the recent, widespread use of opiate medications has led to an increase in opiate addiction and deaths from opiate overdose. Therefore, we believe by providing a safe alternative for pain relief, a PKCe inhibitor could improve the quality of life for military personnel and Veterans who suffer from pain.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810390
Entities
People
- Jon Levine
Organizations
- United States Army
- University of California, San Francisco