Targeted protein degradation has largely relied on the ubiquitin–proteasome system, limiting accessible targets. Here, we introduce methylarginine targeting chimeras (MrTACs), a new class of small molecules that recruit PRMTs to install lysosome-targeting degrons. MrTACs induce robust, selective degradation of diverse and previously intractable proteins via microautophagy. This work establishes lysosomal proteolysis as a complementary, therapeutically viable pathway, expanding the degrader toolbox and enabling access to challenging disease-relevant targets.

I will describe our 1,4,5-trisubstituted imidazole that has high selectivity and potency for the N-terminal bromodomain of BRD4 (BRD4 D1 Kd = 46 nM) over the other seven BET bromodomains.  This inhibitor is better tolerated against thrombocytopenia versus pan-BET inhibitors. I will further describe our BRD4-selective degrader, as well as a new tumor-selective approach using the E3-ligase associated protein MAGEA11 making these unique PROTACs for the field.

TP53 mutations drive ~50% of cancer deaths, typically via missense mutations that paradoxically increase p53 protein. We exploited this abundance using an induced proximity strategy: a bifunctional molecule linking a TP53-Y220C binder to a PLK1 inhibitor concentrates toxicity selectively in mutant cells. The resulting ternary complex mislocalizes PLK1, induces G2/M arrest, and triggers apoptosis in TP53-Y220C cells while sparing wild-type, offering a generalizable framework for targeting missense mutant p53.