Rewiring DNA repair with PARP-based chemical inducers of proximity

Chemical inducers of proximity (CIPs) can elicit durable-and often neomorphic-biological effects through the formation of a ternary complex, even at low equilibrium occupancy of their targets. This "event-driven" pharmacology is exemplified by CIPs that promote targeted protein degradation, but other applications remain underexplored. We developed a generalizable strategy to discover event-driven CIPs by tracking the cellular effects of heterobifunctional small molecules alongside quantitative measures of intracellular target engagement. Using this approach, we discovered PCIP-1, which inhibits DNA repair by recruiting BET proteins to PARP2. Unlike conventional PARP inhibitors, PCIP-1 activity is observed at low equilibrium occupancy of PARP1/2 and without inhibition of PARP-catalyzed PARylation, yet it retains synthetic lethality in cancer cells with homologous recombination deficiencies. PARP1 knockout, which confers resistance to conventional PARP drugs, increases sensitivity to PCIP-1, offering a potential new mechanism to overcome clinical resistance. Through these studies, we demonstrate that DNA repair can be rewired by CIPs and introduce a new form of event-driven pharmacology.