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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Chemotherapies targeting genome instability often disrupt the DNA damage response (DDR) to induce cancer cell death.
• PARP inhibitors (PARPi) are effective against homologous recombination-deficient cancers but have limited indications and acquired resistance.
• Existing PARPi strategies are limited in scope and susceptible to resistance mechanisms.

Purpose of the Study:

• To introduce novel bivalent molecules, DNA damage chemical inducers of proximity (DD-CIPs), that rewire PARPi mechanisms.
• To explore the potential of DD-CIPs in overcoming limitations of conventional PARPi therapy.
• To establish chemical-induced proximity as a viable strategy for modulating the DDR in cancer treatment.

Main Methods:

• Development and screening of a candidate library of DD-CIPs.
• Investigating the mechanism of action involving induced proximity between PARP1/2 and BRD4.
• Evaluating DD-CIP efficacy in vitro and in vivo using cancer cell lines and preclinical models, including small-cell lung cancer (SCLC).

Main Results:

• Identification of DD-CIP1 and DD-CIP2 with potent induction of DDR and apoptosis in cancer cells at nanomolar concentrations.
• Demonstration of DD-CIP2's efficacy across diverse cancer types, including those insensitive to traditional PARPi.
• Preclinical efficacy of DD-CIP2 in SCLC models, showing tumor cell death, cell cycle arrest, and apoptosis without significant toxicity.

Conclusions:

• DD-CIPs represent a novel class of molecules that leverage chemical-induced proximity to modulate the DDR.
• This strategy offers a promising avenue to address the limitations of current PARPi therapies and expand their clinical utility.
• DD-CIPs demonstrate potential for treating a broader spectrum of cancers, including those resistant to existing treatments.