Design and Development of DNA Damage Chemical Inducers of Proximity (DD-CIP) for Targeted Cancer Therapy

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Chemotherapies target genome instability in cancer cells.
• PARP inhibitors (PARPi) are effective against HR-deficient cancers but have limited indications and acquired resistance.
• Novel strategies are needed to enhance DNA damage response (DDR) induction in cancer therapy.

Purpose of the Study:

• To introduce a new class of molecules, DNA Damage Chemical Inducers of Proximity (DD-CIPs), that leverage chemical induced proximity to modulate PARP1/2 activity.
• To evaluate the efficacy of DD-CIPs, specifically DD-CIP1 and DD-CIP2, in inducing cancer cell death and overcoming PARPi resistance.
• To assess the therapeutic potential of DD-CIP2 in preclinical models, including small-cell lung cancer (SCLC).

Main Methods:

• Development and screening of a DD-CIP candidate library.
• Investigating the mechanism of DD-CIPs, focusing on induced proximity between PARP1/2 and BRD4.
• Assessing DD-CIP-induced DNA damage response (DDR), apoptosis, and cell cycle arrest in vitro.
• Evaluating anti-tumor efficacy and toxicity of DD-CIP2 in preclinical SCLC xenograft models.

Main Results:

• DD-CIP1 demonstrated nanomolar efficacy in inducing DDR and apoptosis across various cancer cell lines.
• DD-CIP2 showed potent tumor cell death induction at nanomolar concentrations in diverse cancer types, including PARPi-insensitive cancers.
• DD-CIP2 effectively triggered DDR, cell cycle arrest, and apoptosis in SCLC models in vitro, with significant anti-tumor efficacy and low toxicity in vivo.

Conclusions:

• DD-CIPs represent a novel approach to cancer therapy by rewiring PARPi mechanisms through chemical induced proximity.
• DD-CIP2 exhibits broad-spectrum anti-cancer activity and overcomes resistance to conventional PARPi.
• Chemical induced proximity is a viable strategy for modulating the DNA damage response for cancer treatment.