Design and Development of DNA Damage Chemical Inducers of Proximity for Targeted Cancer Therapy

Many chemotherapies are effective against cancers that display high levels of genome instability by disrupting or overwhelming the DNA damage response (DDR) to induce cell death. PARP inhibitors (PARPi) exploit this vulnerability by stalling DNA repair, particularly in homologous recombination-deficient cancer cells. Although PARPi are now used to treat BRCA1/2-mutated cancers such as ovarian and breast cancers, they are still limited to a narrow range of clinical indications and are susceptible to acquired resistance. Here, we introduce "DNA damage chemical inducers of proximity" (DD-CIPs), bivalent molecules that rewire the mechanism of action of conventional PARPi. The DD-CIPs function through chemically induced proximity between PARP1/2 and the chromatin remodeling protein, BRD4. From a candidate library of DD-CIPs, we identified DD-CIP1, which induces the DDR and apoptosis in cancer cells at two-digit nanomolar concentrations. Further optimization yielded DD-CIP2, which induces tumor cell death at nanomolar concentrations across diverse blood and solid cancer cells, including cancer types that are insensitive to PARPi. Using small-cell lung cancer (SCLC) as a model, we found that DD-CIP2 triggers DDR, cell cycle arrest, and apoptosis <i>in vitro</i>, leading to antitumor efficacy without substantial toxicity in preclinical SCLC xenograft models at well-tolerated doses. Our findings demonstrate that DD-CIPs may provide an opportunity to address the limitations of traditional PARPi and establish chemical-induced proximity as a strategy for modulating the DDR in cancer.