Discovery of PSD95 protein-protein interaction inhibitors as novel non-opioid analgesics

Project Summary This application, “Discovery of PSD95 protein-protein interaction inhibitors as novel non-opioid analgesics”, addresses the critical need for more effective medications to treat chronic neuropathic pain. Pain is responsible for more encounters with the health care system than any other single cause, yet treatment options for neuropathic pain have limited efficacy and carry a high risk for side effects, including opioid addiction. These factors add an additional $560-635 billion annually to an already strained United States health care system. Glutamate activation of N-methyl-D-aspartate (NMDA) receptors mediates central nervous system (CNS) sensitization, which is implicated in the development and maintenance of neuropathic pain. NMDA-mediated central sensitization depends on formation of a multi-protein cascade complex at the receptor consisting of the NMDA receptor bound to the scaffolding protein, postsynaptic density protein 95 (PSD95), and recruitment of neuronal nitric oxide synthase (nNOS). By bringing these proteins close together, multiple signaling cascades are activated leading to neural network reorganization (plasticity) and neuronal cell death. Small molecules and cell penetrating peptides that disrupt this complex act as effective analgesics in preclinical animal models with better side effect profiles than non-selective NMDA receptor antagonists and NOS inhibitors. Our team, the first to publish a small molecule targeting this complex, IC87201, demonstrated its efficacy in preclinical pain models. A similar small molecule, ZL006, is effective in preclinical stroke models. We designed and synthesized a unique and novel set of IC87201 and ZL006 analogs, advancing one molecule into IND-enabling studies for post- traumatic stress disorder. After identifying concerns with the candidate molecule, we systematically redesigned it resulting in a new set of molecules. Further funding is needed to improve on these molecules prior to advancing them toward new IND-enabling studies. Importantly, advanced toxicology studies with the candidate molecule suggest a low risk of target specific side effects and predict an excellent therapeutic index for compounds with acceptable activity and drug-like properties. In this SBIR Phase I/II fast track application, Anagin, in concert with our collaborators and the Blueprint Neurotherapeutics Network, will design and test molecules for improved drug- like properties, confirm target engagement in in vitro and ex vivo assays, demonstrate efficacy in preclinical pain models and establish a therapeutic margin using behavioral models. We will advance a new clinical candidate molecule through IND-enabling studies. Compounds that do not meet our set criteria will not be advanced. At the conclusion of these studies, we will have a new clinical candidate thoroughly interrogated and poised for testing in clinical trials for chronic pain. Data summarized in this proposal strongly suggests that our approach will yield effective analgesics with better therapeutic indices than other compounds in development or the clinic. These compounds are likely to be useful in many other glutamate-driven CNS diseases.Project Narrative Chronic pain is a major health crisis for millions of Americans in part due to ineffective treatments with significant side effects. Our non-opioid approach targets a specific pathway which we believe will lead to new drugs that are safe and effective. We have assembled a team of highly experienced researchers to solve this difficult problem and advance these new compounds toward clinical trials.