Discovery of a novel benzofuran-7-carboxamide-based PARP1/c-Met dual inhibitor for addressing c-Met...

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Poly (ADP-ribose) polymerase 1 (PARP1) is a key target in cancer therapy via synthetic lethality.
• Drug resistance, particularly through c-Met amplification, limits the effectiveness of current PARP1 inhibitors.
• Developing novel therapeutics is crucial to overcome resistance mechanisms and improve antitumor efficacy.

Purpose of the Study:

• To design and synthesize a novel dual inhibitor targeting both PARP1 and c-Met.
• To evaluate the potency and drug-like properties of the novel dual inhibitor.
• To assess the in vivo antitumor efficacy of the dual inhibitor in a relevant preclinical model.

Main Methods:

• Derivation of a novel dual inhibitor from the benzofuran-7-carboxamide scaffold of Mefuparib.
• Biochemical assays to determine the inhibitory activity against PARP1 and c-Met (IC50 values).
• Evaluation of antitumor efficacy using HCT116OR xenograft models.

Main Results:

• Compound S12, a novel PARP1/c-Met dual inhibitor, was developed with improved molecular weight and solubility compared to previous compounds.
• S12 demonstrated potent inhibition against PARP1 (IC50 = 21.8 nM) and c-Met (IC50 = 30.2 nM).
• S12 exhibited significant antitumor efficacy in HCT116OR xenograft models.

Conclusions:

• Targeting both PARP1 and c-Met simultaneously is an effective strategy to overcome PARP1 inhibitor resistance.
• Compound S12 represents a promising therapeutic candidate for cancers exhibiting c-Met amplification-mediated resistance.
• Dual inhibition offers a potential approach to enhance the efficacy of cancer therapies.