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First-in-Class NADH/Ubiquinone Oxidoreductase Core Subunit S7 (NDUFS7) Antago

Pancreatic cancer cells adapt to nutrient-scarce metabolic conditions by increasing their oxidative phosphorylation reserve to survive. Here, we present a first-in-class small-molecule NDUFS7 antagonist that inhibits oxidative phosphorylation (OXPHOS) for the treatment of pancreatic cancer. The lead compound, DX2-201, suppresses the proliferation of a panel of cell lines, and a metabolically stable analogue, DX3-213B, shows significant efficacy in a syngeneic model of pancreatic cancer. Exome sequencing of six out of six clones resistant to DX2-201 revealed a pV91M mutation in NDUFS7, providing direct evidence of its drug-binding site. In combination studies, DX2-201 showed synergy with multiple metabolic modulators, select OXPHOS inhibitors, and PARP inhibitors. Importantly, a combination with 2-deoxyglucose overcomes drug resistance in vivo. This study demonstrates that an efficacious treatment for pancreatic cancer can be achieved through inhibition of OXPHOS and direct binding to NDUFS7, providing a novel therapeutic strategy for this hard-to-treat cancer.

 

Comments:

The findings you've shared represent a significant advancement in pancreatic cancer treatment. Targeting the adaptive mechanisms of cancer cells, particularly their increased reliance on oxidative phosphorylation (OXPHOS) under nutrient-scarce conditions, could indeed offer a promising therapeutic avenue.

The small-molecule NDUFS7 antagonist, specifically DX2-201 and its metabolically stable analogue DX3-213B, demonstrates substantial potential. These compounds not only suppress cell line proliferation but also exhibit efficacy in a syngeneic model of pancreatic cancer. The identification of the pV91M mutation in NDUFS7 among resistant clones directly links it to the drug-binding site, offering compelling evidence of its mechanism of action.

Furthermore, the observed synergy between DX2-201 and various metabolic modulators, select OXPHOS inhibitors, and PARP inhibitors in combination studies suggests a multi-pronged approach to treatment. Especially noteworthy is the overcoming of drug resistance in vivo through a combination with 2-deoxyglucose, underscoring the potential for combination therapies to enhance efficacy.

Overall, this study highlights the significance of targeting OXPHOS and NDUFS7 inhibition as a novel therapeutic strategy for pancreatic cancer, providing hope for improved treatments in an otherwise challenging-to-treat cancer type. The ability to tackle resistance mechanisms and enhance efficacy through combination therapies adds further depth to the potential clinical impact of these findings.

Related Products

Cat.No. Product Name Information
E1139 DX3-213B DX3-213B is a highly potent, orally active oxidative phosphorylation (OXPHOS) complex I inhibitor with IC50 of 3.6 nM, and impairs ATP generation with IC50 of 11 nM.

Related Targets

OXPHOS