PRL3 inhibitors as migrastatics and the molecular determinants of PRL3 druggability

Project Summary More than 90% of cancer mortalities are associated with metastasis. Despite advances in cancer therapies, there has not been significant progress in metastasis-associated deaths and there are not a lot of targeted treatment options for late-stage patients. It has been challenging to target metastasis due to the complexity of underlying

mechanisms that lead to it. The phosphatase of regenerating liver 3, PRL3, has emerged as one of the most promising cancer targets in recent years. It was originally identified as a biomarker for metastasis in colorectal cancers. Interestingly, it has been implicated in increased invasiveness and metastatic potentials in several other

cancers. While its biological functions remain to be elucidated, studies in cancer models, patient data, and known substrates all indicate that it has an active role in cellular invasiveness and metastasis. PRL3, therefore, presents as a valuable molecular target in metastasis. The long-term goal of this project is to develop

migrastatics that specifically target PRL3. Given increasing interests in phosphatase drug discovery, particularly those that have been linked to cancers, several PRL3 inhibitors have been identified over the past several years. The promiscuity, non-specific action, and chemical instability of these molecules, however, have prevented

further development. More striking, though, is that none of these inhibitors have been shown to directly bind PRL3. This prohibits the development of high affinity, selective inhibitors by rational design and optimization as no atomic level information is available as to how PRL3 interacts with its inhibitors. Our group recently identified

two inhibitors that directly and specifically bind PRL3, the first such inhibitors. The objective of this proposal is to uncover the molecular determinants of PRL3 druggability and to identify novel molecules with potential to be developed as migrastatics. The rationale for the proposal is that structural information is critical for rational

drug design, and binders are necessary to get such structural information. Furthermore, this will provide molecular mechanism of action for potential migrastatics that will be identified. This will be accomplished through the following specific aims: 1) determine the structure of PRL3 in complex with inhibitors, 2) improve the current

molecules through structure activity relationships, and 3) identify novel fragments through a binding-first screening by NMR. This proposed research is significant as it will directly contribute to the development of molecular targeted migrastatics which has high