Rewiring DNA repair with PARP-based chemical inducers of proximity

da Camara, B.; Bilotta, E. M.; Broderick, E. F.; Premashankar, A.; Barta, P. A.; Carter, T. R.; Hargis, L. M.; Durocher, D.; Erb, M. A.

doi:10.1101/2025.07.26.666954

bioRxiv · 10.1101/2025.07.26.666954

Rewiring DNA repair with PARP-based chemical inducers of proximity

da Camara, B.·Bilotta, E. M.·Broderick, E. F.·Premashankar, A.·Barta, P. A.·Carter, T. R.·Hargis, L. M.·Durocher, D.·Erb, M. A.

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Abstract

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.

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da Camara, B., Bilotta, E. M., Broderick, E. F., Premashankar, A., Barta, P. A., Carter, T. R., Hargis, L. M., Durocher, D., Erb, M. A.. 2025-07-31. Rewiring DNA repair with PARP-based chemical inducers of proximity. https://doi.org/10.1101/2025.07.26.666954

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