Dual PARP/NAMPT Inhibitors for BRCA Wild-Type Triple-Negative Breast Cancer: Disrupting Homologous Recombination...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Simultaneous inhibition of PARP and NAMPT offers synergistic efficacy in BRCA wild-type Triple-Negative Breast Cancer (TNBC) via synthetic lethality.
• This strategy broadens the clinical applications of PARP inhibitors.

Purpose of the Study:

• To rationally design and optimize novel dual PARP/NAMPT inhibitors.
• To evaluate the efficacy and mechanism of action of a lead compound (10n) in BRCA wild-type TNBC models.

Main Methods:

• Design and synthesis of dual PARP/NAMPT inhibitors.
• In vitro assays to determine inhibitory concentrations (IC50) and cell proliferation inhibition.
• In vivo studies using xenograft and metastatic cancer models.
• Analysis of DNA damage, apoptosis, immunogenic cell death (ICD), and cGAS-STING pathway activation.

Main Results:

• Compound 10n demonstrated potent dual inhibition of PARP1 and NAMPT (IC50 = 1.2 and 6.7 nM).
• 10n effectively inhibited BRCA wild-type TNBC cell proliferation, disrupted DNA repair, induced double-strand breaks, and promoted apoptosis.
• In vivo, 10n·HCl showed significant antitumor activity in xenograft models and reduced lung metastasis.
• 10n·HCl induced immunogenic cell death and activated the cGAS-STING pathway, enhancing antitumor immunity.

Conclusions:

• Compound 10n is a promising lead candidate for developing dual PARP/NAMPT inhibitors.
• This approach holds potential for treating BRCA wild-type TNBC and stimulating anti-tumor immune responses.