This summer I continued my project from last summer of screening for small ubiquitin-like modifier (SUMO)-specific protease inhibitors. Small ubiquitin-like modifier (SUMO) becomes covalently conjugated to target proteins in a process called sumoylation. Desumoylation involves removal of the SUMO-moiety from target proteins. In higher eukaryotes, there are three related SUMO: SUMO-1, -2 & -3. Sumoylation modifies the physical properties and the cellular functions of the target proteins. These modifications affect intracellular localization, protein-protein interactions, and other post-translational processes. These changes in turn affect gene expression, genomic and chromosomal stability and integrity, and signal transduction. In humans, sumo-specific proteases (SENPs) are necessary for the sumoylation-desumoylation cycle. SENP cleaves a peptide bond within the SUMO protein to active and prepare it for conjugation. In addition, SENP cleaves the SUMO-moiety from SUMO-modified target proteins to reverse the sumoylation process. There are seven known human SENPs. SENPs are cysteine proteases which share a common catalytic mechanism: using a nucleophilic cysteine thiol in a catalytic triad to cleave peptide bonds. In this study, we focused on SENP1 and SUMO-1. Recent research identified two links between SENP1 and cancer. One study showed that androgen receptor (AR) sumoylation is dynamic and reversed by SENP1 and that desumoylation promotes AR-dependent transcription in prostate cancer cells. Another study examining SENP1-/- mice embryos found that SENP1 regulates the stability of hypoxia-inducible factor 1α (HIF1α) during hypoxia. Thus, by finding inhibitors for SENP1 we may be able to modulate AR-dependent transcription in prostate cancer cells and/or regulate HIF1α stability, which is important in multiple solid tumors. This summer we screened 30,000 compounds.