Pyridine based MYC degraders truncate endogenous MYC proteins and shift the balance of the MYC proteome

MYC is a DNA binding transcription factor whose sustained dysregulation promotes the initiation and maintenance for numerous cancers. Small molecules directly binding and blocking the disordered MYC monomer from forming critical protein interactions have supplied numerous probes highlighting the complexities of inhibiting this monumental target and have helped legitimize MYC as a tractable therapeutic target. Unfortunately, most of the inhibitors that have shown promise in pre-clinical settings have not made significant advances towards practical clinical applications. The rise of proximity induced pharmacology has lent new opportunities to understand complex biological pathways and vulnerabilities to help target proteins like MYC where small molecule inhibition has proved challenging. We demonstrate the application of proximity inducing heterobifunctional PROteolysis TArgeting Chimeras (PROTACs) towards regulating concentrations of oncogenic MYC monomers derived from the pyridine scaffold of MYC inhibitor, KJ-Pyr-9. We found MTP3 depletes endogenous full-length MYC proteins and uniquely exacerbates levels of a functional, N-terminally truncated MYC species, tMYC. MTP3 destabilizes the MYC proteome in favor of a tMYC dominant cell state with a distinct regulatory landscape. Our results highlight the complexities of proximity-induced chemistry against highly regulated and dynamic protein targets like MYC and indicate that PROTACs can regulate alternative outcomes beyond target protein degradation.