Abstract LB025: DNA damage chemical inducers of proximity (DD-CIP) for targeted cancer therapy

Abstract Many cancer therapies preferentially kill tumor cells with high genome instability by overwhelming DNA damage response (DDR) pathways and triggering cell death. PARP inhibitors (PARPi) exploit this vulnerability by impairing DNA repair, particularly in homologous recombination (HR) -deficient cancer cells, such as BRCA1/2-mutated ovarian and breast cancers. However, the therapeutic scope of PARPi often remains limited in HR-proficient cancers and is frequently undermined by acquired resistance. New strategies that reprogram DDR signaling to extend the utility of PARP-based therapies across broader cancer contexts are unmet need. Here, we present DNA Damage Chemical Inducers of Proximity (DD-CIPs), the bivalent small molecules that enforces proximity between PARP1/2 and the chromatin regulator proteins (BRD4) to rewire downstream DDR signaling. Lead DD-CIP molecules can induce robust DDR, cell-cycle arrest, and apoptotic cell death in PARP1/2-BRD4 interaction dependent manner. Further optimization leads to DD-CIP2 that induces tumor cell death at nanomolar concentrations across a broad panel of hematologic and solid tumor cell lines, including cancer types that are insensitive to PARPi. To further evaluate the therapeutic potential of DD-CIP2, we selected small-cell lung cancer (SCLC) as a representative solid tumor model, as this subtype of cancer showed hypered DNA replication stress response despite HR-proficiency. Thus, this provides us with an opportunity to evaluate DD-CIP2 activity in a HR-proficient context. We showed that DD-CIP2 treatment results in potent anti-tumor activity in vitro and significant tumor growth suppression in xenograft studies at well-tolerated doses, without evidence of substantial systemic toxicity. Together, these findings establish CIP as a strategy for reprogramming DDR and overcoming limitations of current PARP inhibitor therapies in cancer, suggesting its potential for a broader clinical benefit. Citation Format: Tian Qiu, Yeuan Ting Lee, Brendan G. Dwyer, Yi Jer Tan, Ting Chen, Bryan A. Romero, Yanlan Wang, Jiehui Deng, Tinghu Zhang, Gerald R. Crabtree, Stephen M. Hinshaw, Kwok-Kin Wong, Nathanael S. Gray. DNA damage chemical inducers of proximity (DD-CIP) for targeted cancer therapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB025.