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

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Discovery and Lead Optimization of Benzene-1,4-disulfonamides as Oxidative Phosphorylation Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-01-04 , DOI: 10.1021/acs.jmedchem.1c01509
Ding Xue ₁ , Yibin Xu ₁ , Armita Kyani ₁ , Joyeeta Roy ₁ , Lipeng Dai _{1,

2} , Duxin Sun _{1,

2} , Nouri Neamati ₁

Affiliation

Inhibition of oxidative phosphorylation (OXPHOS) 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.

中文翻译：

苯-1,4-二磺胺作为氧化磷酸化抑制剂的发现和先导优化

抑制氧化磷酸化（OXPHOS）对于依赖有氧代谢的特定癌症来说是一种很有前途的治疗策略。在这里，我们报告了一系列新型 OXPHOS 抑制剂的发现、优化和构效关系 (SAR) 研究。命中化合物苯-1,4-二磺酰胺1是在含半乳糖培养基中对细胞毒性有选择性的表型筛选中发现的。我们的多参数优化活动导致了65 ( DX3-235 ) 的发现，显示了在含半乳糖的培养基中对复合物 I 功能和三磷酸腺苷 (ATP) 产生的纳摩尔抑制，从而导致显着的细胞毒性。重要的是，64 ( DX3-234) 是65的紧密类似物，在小鼠中具有良好的耐受性，并且在 Pan02 同基因胰腺癌模型中显示出显着的单药疗效，这表明高效和选择性的 OXPHOS 抑制剂可用于治疗胰腺癌。

更新日期：2022-01-13

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