PROTACs are hetero-bifunctional compounds that link a ligand for E3 ubiquitin ligase and another ligand for target proteins. Many PROTACs recruit CRL4CRBN and CRL2VHL to the target proteins and induce poly-ubiquitylation and proteasomal degradation of the target proteins.
We have developed IAP-based PROTACs, named SNIPERs, to induce targeted protein degradation. IAPs are a family of proteins that has baculoviral IAP repeat (BIR) domains. Among the eight human IAP family members, some IAP members contain RING finger domain (cIAP1, cIAP2, XIAP, Livin and ILP2) and another member contains an UBC domain (Apollon), and they are supposed to be involved in the ubiquitylation of themselves and associated proteins.
In our early studies we used bestatin as a ligand for cIAP1 to develop SNIPERs (1st-generation SNIPERs), and then we employed a pan-IAP antagonist LCL-161 resulting in the SNIPERs with a more potent degradation activity (2nd-generation SNIPERs).
In contrast to the CRL4CRBN and CRL2VHL that generate K48-linked polyubiquitin chains, IAPs generate K63- and K48-linked poly-ubiquitin chains. Since K63-linked polyubiquitin chain is not a signal for proteasomal degradation, we reasoned that SNIPERs may be able to induce different cellular responses other than the proteasomal degradation.
In the symposium, I will explain recent data showing that SNIPERs induce diverse cellular responses and discuss the mechanisms underlying these responses.