Discovery and Lead Optimization of Benzene-1,4-disulfonamides as Oxidative Phosphorylation Inhibitors

Abstract

Inhibition of oxidative phosphorylation (OX-PHOS) is a promising therapeutic strategy for select cancers that are dependent on aerobic metabolism. Here, we report the discovery, optimization, and structure−activity relationship (SAR) study of a series of novel OXPHOS inhibitors. The hit compound, benzene-1,4-disulfonamide 1, was discovered in a phenotypic screen selective for cytotoxicity in a galactose-containing medium. Our multi-parameter optimization campaign led to the discovery of 65 (DX3-235), showing nanomolar inhibition of complex I function and adenosine triphosphate (ATP) production in a galactose-containing medium resulting in significant cytotoxicity. Importantly, 64 (DX3-234), a close analogue of 65, is well tolerated in mice and shows significant single agent efficacy in a Pan02 syngeneic pancreatic cancer model, suggesting that highly potent and selective OXPHOS inhibitors can be useful for the treatment of pancreatic cancer.

Multiparameter Optimization of Oxidative Phosphorylation Inhibitors for the Treatment of Pancreatic Cancer

“…Our previous study suggested that de-ethylation is a possible metabolic pathway of this series of compounds. 35 We hypothesized that the newly introduced electrodeficient 4,4difluoropiperidine would not likely be a metabolic soft point. Therefore, we designed corresponding sulfones or monosubstituted sulfonamides to address metabolic liabilities.…”

“…The filtrate was concentrated and purified with flash chromatography (20% EtOAc in hexane) to give 34 as a yellow solid (520 mg, 91%). 4-(N,N-Diethylsulfamoyl)benzenesulfonyl Chloride (35). To an ice-cooled solution of 34 (100 mg, 0.30 mmol) in a mixture of CH 3 CN (2.5 mL), HOAc (0.16 mL), and H 2 O (0.1 mL) was added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (117 mg, 0.60 mmol) portionwise.…”

“…34 We recently reported the discovery of a series of novel benzene-1,4-disulfonamides as a new class of complex I inhibitors represented by DX3-234 (Figure 1). 35 Despite the promising in vivo efficacy of several complex I inhibitors in various cancers, currently no selective OXPHOS inhibitor has been FDA-approved. In our previous work, compound 1 was discovered through a phenotypic screen selective for cytotoxicity in cells grown in galactose-containing media instead of glucose-containing media.…”

“…In our previous work, compound 1 was discovered through a phenotypic screen selective for cytotoxicity in cells grown in galactose-containing media instead of glucose-containing media. 35 Our initial optimization campaign produced oxetanyl amide 2 with improved metabolic stability and significant inhibition of MIA PaCa-2 cell proliferation in the low micromolar range (Figure 2). Further modifications of the amide moiety to pursue extended interactions led to the discovery of a series of optimized compounds (Figure 2; series I) represented by DX3-234 (Figure 1) with significantly improved potency and metabolic stability.…”

Emerging Trends and Research Foci in Tumor Microenvironment of Pancreatic Cancer: A Bibliometric and Visualized Study

“…In addition, studies have shown that mTORC1 and other substances can affect glutamine synthetase to inhibit the synthesis of glutamine, further inhibit the nutrient uptake of pancreatic cancer cells, and reduce the proliferation ability of PDAC ( 48 ). At present, DX3-235, DX3-213B and other targeted oxidative phosphorylation inhibitors can effectively inhibit the growth of pancreatic cancer cells in the low nanomolar range and have no obvious toxicity ( 49 ). Therefore, it was believed that targeting the hypoxic microenvironment of PDAC, employing a multimodal therapeutic approach and developing biointegration targets, and remodeling the TME are promising strategies.…”