According to data provided by the CDC, metastatic cancers are the second leading cause of death in the U.S. With modern innovations in molecular biology and genomic sequencing, researchers are developing targeted therapies that can selectively inhibit agents involved in the formation and propagation of cancer. The regulatory role of serine/threonine phosphatase-5 (PP5) in signaling cascades controlling cell growth and metabolism makes PP5 an attractive target for drug development. To identify novel inhibitors of PP5, a homogeneous fluorescence intensity-based biochemical assay was developed. Structural analysis of hits from an ultra-high-throughput screen of over 315,000 compounds revealed that the most potent compounds confirmed as PP5-selective inhibitors share a common (7-oxabicyclo[2.2.1]heptane) core, which modeling suggested could be elaborated at either the C5 or C6 position to improve selectivity versus PP1 and PP2A. Novel C5/C6-derivatives were synthesized. Co-crystal structures of PP5 in complex with two of these derivatives revealed close contacts between the inhibitor bridgehead oxygen and both a catalytic metal ion and a non-catalytic phenylalanine residue, which is substituted by tryptophan in PP4. Quantum chemistry calculations predicted that steric clashes with the bulkier tryptophan side chain would disrupt the strong coordination of active site metal ions observed in PP5 co-crystal structures and thereby render PP4 insensitive to this class of inhibitors. This was confirmed by inhibition studies employing native human PP4C. In addition, a single point mutation of PP5 to mimic the active site of PP4 was found to render PP5 insensitive to 7-oxabicyclo[2.2.1]heptane-based inhibitors.

Phosphoprotein phosphatases: Novel targets for therapeutic cancer treatments

251st National Meeting (2016)

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