Discovery of Novel Glutaminase (GLS1) and Histone Deacetylase (HDAC) Dual Inhibitors as a Promising Strategy for Cancer Therapy
Zhisheng Zhang, Xuan Zhang, Yinan Jiang, Manqi Zhang, Juan Zhao, Tianxin Li, Jiani Yang, Shengnan Shi, Xueling Cao, Lingxiang Jiang, Zihan Tian, Yongsheng Wu, Jiawen Ru, Liuxiang Zhu, Qianming Du, Jinlei Bian, Zhiyu Li, Xi Xu, Jubo WangAbstract
Glutaminase 1 (GLS1) and histone deacetylases (HDACs) are important targets involved in cancer metabolism and epigenetic regulation, respectively. Herein, we report the design, synthesis, and biological evaluation of first-in-class GLS1/HDAC dual inhibitors as a single-molecule strategy for cancer therapy. Through systematic structure-activity relationship studies and biochemical profiling, compound 58 was identified as a promising dual inhibitor with moderate GLS1 inhibition and potent HDAC activity, particularly against HDAC6. Compound 58 exhibited strong antiproliferative activity in multiple cancer cell lines and modulated GLS1-associated glutamine metabolism and HDAC-related acetylation markers in cells. In a CT26 tumor-bearing mouse model, compound 58 achieved a tumor growth inhibition (TGI) rate of 91.10% without obvious systemic toxicity. Overall, this study supports GLS1/HDAC dual inhibition as a promising anticancer strategy and provides compound 58 as a valuable lead for further optimization.