The goal of this research program is to develop a novel small molecule inhibitor of latent Epstein-Barr Virus (EBV) infection. EBV is a ubiquitous gamma- herpesvirus that has been classified by the World Health Organization as a human carcinogen. Vironika, with its consortium partners the Wistar Institute and Fox Chase Chemical Diversity Center, Inc., will develop a highly specific and potent inhibitor of EBV latency that wil provide an important therapeutic strategy to treat EBV-associated diseases. Latent infection is associated with multiple human malignancies, including Burkitt's lymphoma, nasopharyngeal carcinomas, Hodgkin's lymphoma, gastric carcinomas, and immunoblastic B-cell lymphoma's during immunosuppression. Currently, no EBV-specific therapies exist that target latent infection, and therefore it remains impossible to effectively treat or prevent EBV-associated disease. The latent infection depends on a viral encoded protein which functions in the replication and maintenance of the viral genome. Genetic and biological disruption of this protein blocks viral latent infection and EBV-dependent B-cell growth. The binding domain of this protein has been characterized structurally and biochemically, and serves as an ideal molecule for targeted small molecule inhibition of EBV infection. We have screened over 600,000 compounds in our primary HTS screen and identified one lead. In parallel, we have discovered another lead molecule using a fragment-based approach. These leads have high potency, selectivity and wide safety margins. In this Phase 2 application, we propose to use an iterative process for lead optimization. We will synthesize analogues, test their efficacy in in viro and cell-based assays, and monitor their ADME liabilities. Lead analogs will then be tested to determine pharmacokinetic properties, toxicity and efficacy in a mouse model. For each round, we will optimize the efficacy and potency of the chemotypes and mitigate toxicity or other liabilities. The goal of this Phase 2 project is to identify one pre-clinical candidate with which e can perform IND-enabling studies to take into Phase 1 first-in-man clinical trials.
The research program described in this proposal will reduce the incidence of latent (non-active) infection by Epstein-Barr Virus (EBV). Latent EBV has been classified as a human carcinogen and is associated with nasopharyngeal carcinomas, Burkitt's lymphoma, and Hodgkin's lymphoma. The product being developed in this proposal is the first therapeutic small molecule drug that specifically disrupts EBV latent infection.