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
