STAT3を分解するPROTAC/SNIPERの分子設計、合成と活性評価

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Proteolysis targeting chimera (PROTAC) is a technology that uses chimeric chemicals to bind to a protein of interest (POI) and an E3 ligase so as to induce POI degradation through the ubiquitin-proteasome system. In this project, we intended to develop novel PROTAC degraders targeting STAT3.First, we employed sulfonamide derivatives that are believed to bind to the SH2 domain of STAT3 as small molecule-warheads and synthesized PROTACs by conjugating to thalidomide (a cereblon E3 ligase binder) via alkyl linkers. The molecular weights of the resulting PROTACs are approximately 900. Then, the STAT3 degradation activity of these PROTACs were tested along with their parental STAT3 binders in MCF7 and SU-DHL-1 cells. The western blot analysis indicated that PS314 (PROTAC, using PS313 as a warhead) showed a significant activity to reduce STAT3 protein level in both cell lines, while PS312 (PROTAC, using PS311 as a warhead) did not reduce the STAT3 protein level.We also developed oligonucleotide-warheaded PROTAC molecules against STAT3. A decoy oligonucleotide to which STAT3 binds was conjugated to three different E3 ligands to be LCL-STAT3 decoy, POM-STAT3 decoy and VH-STAT3 decoy. Tested in MCF7 cells, POM-STAT3 decoy was found to be more able to degrade STAT3 than VH-STAT3 decoy, and LCL-STAT3 decoy showed no degradation activity.