Targeting MDM2 homodimer and heterodimer disruption with DRx-098D in TP53 wild-type and mutant cancer cells

Abstract Novel pharmacological strategies capable of inhibiting pro-oncogenic MDM2 beyond its p53-dependent functions represents an increasingly attractive therapeutic strategy to treating solid and haematological cancers that are depdendent upon MDM2/MDMX, regardless of TP53 mutational status. Utilising a novel first-in-class cell-penetrating peptide disruptor of MDM2 homo- and heterodimerisation (DRx-098D), we demonstrate the anti-proliferative effect of blocking MDM2 dimerisation against a a panel of human cancer cell lines that are TP53 wild-type, mutant or null. DRx-098D elicits its anti-cancer activity via a differentiated mechanism vs. Idasanutlin (a Phase III clinical candidate MDM2-p53 small molecule inhibitor), inducing significantly superior growth inhibition against TP53 null HCT116 cells. Our preliminary data highlight, for the first time, the potential therapeutic utility of exploiting MDM2 dimerisation in TP53 wild-type and mutant cancers. Competing Interest Statement CMB and GSB hold patent rights to relevant published work. DTH is a consultant for Triana Biomedicines. The remaining authors declare no competing interests.