Hou Wei, Chen Zhao, Pan Chuqiao, Ni Maowei, Ruan Haoqiang, Song Jun, Lu Shiying, Bhasin Aman, Ruan Benfang Helen
College of Pharmaceutical Science, Collaborative Innovation Center of Yangtza River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, China.
Center for Cancer Research, Zhejiang Cancer Hospital, Hangzhou 310022, China.
ACS Med Chem Lett. 2023 May 3;14(7):920-928. doi: 10.1021/acsmedchemlett.2c00470. eCollection 2023 Jul 13.
Allosteric glutaminase inhibitors demonstrate inhibition of glutamine-dependent cancer cells with low general drug toxicity, but have issues with efficacy . Here, we designed a series of diselenide compounds with 6 atoms in the middle, aiming to target the allosteric site of kidney type glutaminase (KGA) with a covalent linkage to strengthen the interaction. Proteomic analysis demonstrated that the diselenide compounds cross-linked with the Lys320 residue at the KGA allosteric site; this was confirmed by the KGA K320A mutant which showed essentially no binding to the diselenide. Further, structure-activity relationship (SAR) analysis demonstrated that growth inhibition correlated well with KGA inhibition and was enhanced by thioredoxin reductase (TrxR) inhibition. Interestingly, diselenide compounds showed no inhibition of glutamate dehydrogenase (GDH), indicating some enzyme selectivity. Importantly, the designed novel diselenides are glutaminase allosteric inhibitors that showed efficacy and survival in the xenograft animal model.
变构谷氨酰胺酶抑制剂对谷氨酰胺依赖性癌细胞具有抑制作用，且一般药物毒性较低，但存在疗效问题。在此，我们设计了一系列中间含有6个原子的二硒化合物，旨在通过共价连接靶向肾型谷氨酰胺酶（KGA）的变构位点，以加强相互作用。蛋白质组学分析表明，二硒化合物与KGA变构位点的Lys320残基交联；KGA K320A突变体基本不与二硒化合物结合，证实了这一点。此外，构效关系（SAR）分析表明，生长抑制与KGA抑制密切相关，并且通过硫氧还蛋白还原酶（TrxR）抑制而增强。有趣的是，二硒化合物对谷氨酸脱氢酶（GDH）没有抑制作用，表明具有一定的酶选择性。重要的是，所设计的新型二硒化合物是谷氨酰胺酶变构抑制剂，在异种移植动物模型中显示出疗效和生存期延长。
