SBIR-STTR Award

Protein kinase C inhibitors have been rendered as attractive targets for therapeutic agents. Recent studies have been shown that PKC epsilon isozyme is a valid new therapeutic target for treating alcoholism, anxiety and pain related to inflammation and alcoholic polyneuropathy. However, there is no selective inhibitor of PKC epsilon that can be administered systematically and cross the blood-brain barrier. Recently, we have been developing new algorithms and technology platform of computational modeling, optimization and virtual screen to parallel select novel small molecule drug leads with balanced potency and ADMET (absorption, distribution, metabolism, excretion, toxicity) properties. We have performed preliminary studies both in modeling of known inhibitors of PKC isozymes as well as in experimental in-vitro screening. The key pharmacophoric and structural features and their differences, for example, between inhibitions of PKC epsilon and beta2 isozymes have been successfully identified. The convergence of in-vitro and in-silcio (computer-based) studies will allow us to not only better understand the structural and pharmacophoric requirements for discover novel, potent, selective PKC epsilon inhibitors, but also to optimize and select them with balanced ADMET properties in a shorter time and less resources. Our proposed research project will involve further studies to improve and fine-tune these technologies and in-vitro/in-silico iterative processes and explore the utility of them in discovering new, selective, oral- and brain-active PKC epsilon inhibitors for treatment of alcoholism, anxiety and pain.

Thesaurus Terms:
alcoholism antagonist, analgesic, chemical structure function, computational biology, drug design /synthesis /production, isozyme, neuropharmacology, protein kinase C, protein kinase inhibitor alcoholism /alcohol abuse, chemical registry /resource, mathematical model, tranquilizer fluorescence polarization, protein purification

Alcoholism and alcohol abuse are the most common forms of drug abuse and effect about 8% of the U.S. population at a cost of approximately $184 billion a year. Current treatment generally consists of psychosocial therapies aimed at rehabilitation and reducing alcohol-associated problems and pharmacotherapy with a limited number of approved drugs. While current treatment can be effective in reducing alcohol consumption, it is estimated that 40-70% of patients return to excessive drinking within a year after treatment. This is partly due to the modest effectiveness of currently approved medications and their side effects, which contribute to poor compliance with their use. Clearly, there is a need to develop more effective drugs. A large body of preclinical data available through studies of mice deficient in PKC_epsilon and rats treated with a peptide inhibitor of PKC_epsilon provides a strong case for development of PKC_epsilon inhibitors to reduce alcohol self-administration and pain associated with alcoholic polyneuropathy. In addition, evidence indicates that PKC_epsilon inhibitors could be useful for the treatment of anxiety, which is commonly associated with alcoholism and may contribute to excessive drinking. This proposal is focused on the preclinical development of a novel class of small organic compounds that act as inhibitors of the enzyme PKC_epsilon. Currently, there are no selective inhibitors of PKC_epsilon that can be administered systemically and cross the blood-brain barrier. Based on combined multi-property computational modeling and wet-lab verification in our Phase I SBIR study, a water soluble small organic molecule, VMD-C620 was identified as an effective and relatively selective "allosteric" PKC_epsilon inhibitor acting reversibly and noncompetitively with ATP and substrate. VMD-C620 was also shown to be efficacious in an experimental animal model of alcoholic polyneuropathy and exhibited high specificity when assayed against related kinases, including the highly related PKC_epsilon. Its distinctive molecular scaffold is very amenable to modification and optimization by medicinal and computational chemistries. These unique properties make VMD-C620 an excellent candidate to be further derived, optimized and developed for the potential treatment of alcohol use disorders. The project proposed here is to develop more potent derivatives of VMD-C620 and study them in preclinical pharmacokinetic and animal disease models relevant to alcohol use disorders. This work will form the basis for future studies, which will complete preclinical development to allow testing of a novel PKC_epsilon inhibitor in humans as a new and improved agent for treatment of alcohol use disorders.

Thesaurus Terms:
alcoholism /alcohol abuse chemotherapy, chemical structure function, drug design /synthesis /production, drug screening /evaluation, kinase inhibitor, nonhuman therapy evaluation, protein kinase C alcoholism /alcohol abuse, chemical registry /resource, computational biology, drug adverse effect, pharmacokinetics, psychopharmacology, toxicology behavior test, genetically modified animal, laboratory mouse, laboratory rat