Discovery and Structural Basis of the Selectivity of Potent CyclicPeptide Inhibitors of MAGE-A4 br

MAGE proteins are cancer testis antigens (CTAs) thatare characterized by highly conserved MAGE homology domains(MHDs) and are increasingly being found to play pivotal roles inpromoting aggressive cancer types. MAGE-A4, in particular, increasesDNA damage tolerance and chemoresistance in a variety of cancers bystabilizing the E3-ligase RAD18 and promoting trans-lesion synthesis(TLS). Inhibition of the MAGE-A4:RAD18 axis could sensitize cancercells to chemotherapeutics like platinating agents. We use an mRNAdisplay of thioether cyclized peptides to identify a series of potent andhighly selective macrocyclic inhibitors of the MAGE-A4:RAD18interaction. Co-crystal structure indicates that these inhibitors bind ina pocket that is conserved across MHDs but take advantage of A4-specific residues to achieve high isoform selectivity. Cumulatively, ourdata represent thefirst reported inhibitor of the MAGE-A4:RAD18 interaction and establish biochemical tools and structuralinsights for the future development of MAGE-A4-targeted cellular probes