Synthesis and Evaluation of a Potential RSK2 Degrader in Human Multiple Myeloma Cell Lines

Targeted protein degradation (TPD) has emerged as an innovative technology in drug development. In this manuscript, we evaluated LJH685 (an RSK2 ligand) and proteolysis targeting chimeras (PROTACs) based on LJH685 as the first degrader targeting ribosomal S6 kinase 2 (RSK2), a serine/threonine kinase associated with cancer progression. LJH685 decreased total RSK2 via the ubiquitin-proteasome system (UPS) in human multiple myeloma cell lines (HMCLs). Four LJH685-based PROTACs, composed of pomalidomide (a cereblon E3 ligase ligand) and different lengths of polyethylene glycol (PEG) linkers, decreased both total RSK2 and phosphorylated RSK2^Ser227 levels in HMCLs. Among these, PROTAC 2, which features 1 PEG unit as a linker, demonstrated the strongest degradation using cereblon (CRBN) and UPS and anti-proliferative activity, which were comparable to those of LJH685. Molecular docking simulations further supported these findings, revealing that PROTACs with PEG linkers formed stable ternary complexes with RSK2 and CRBN, whereas the linkerless PROTAC, which showed lower activity, was unable to form an appropriate complex. These results emphasize the critical role of linker length in optimizing PROTAC efficacy for targeting RSK2. Future exploration of diverse E3 ligases could enable optimization of PROTAC selectivity.