Sun Hanyu, Du Tingting, Yang Minjian, Liu Xue, Xue Xi, Chen Kai, Lang Xuli, Chen Xiaoguang, Wang Baolian, Wang Xiaojian
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, P. R. China.
Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Department of Medicinal Chemistry, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, P. R. China.
ACS Med Chem Lett. 2023 Sep 28;14(10):1455-1466. doi: 10.1021/acsmedchemlett.3c00375. eCollection 2023 Oct 12.
As glutaminase C (GAC) has become an attractive target for cancer treatment by regulating glutaminolysis, thus, interest in GAC inhibitors has risen in recent years. Herein, a potential binding subpocket comprising basic residues was identified, and through extensive structure-activity relationship studies, promising inhibitors and were identified with robust GAC inhibitory activity and A549 cell antiproliferative activity. X-ray crystallography of the -GAC and -GAC complexes revealed a novel binding mode against GAC. The potency of and against GAC further highlighted the importance of the binding. Notably, compounds and regulated the cellular metabolite, thereby increasing reactive oxygen species by blocking glutamine metabolism. Compound also exhibited excellent antiproliferative activity in the A549 cell xenograft model. We further proved that is a safe GAC allosteric inhibitor. A basic subpocket is proposed that might provide new strategies for the development of novel GAC inhibitors in the future.
由于谷氨酰胺酶C（GAC）通过调节谷氨酰胺分解已成为癌症治疗的一个有吸引力的靶点，因此近年来对GAC抑制剂的兴趣有所增加。在此，鉴定出了一个包含碱性残基的潜在结合亚口袋，并通过广泛的构效关系研究，鉴定出了具有强大GAC抑制活性和A549细胞抗增殖活性的有前景的抑制剂。-GAC和-GAC复合物的X射线晶体学揭示了一种针对GAC的新型结合模式。和对GAC的效力进一步突出了这种结合的重要性。值得注意的是，化合物和调节细胞代谢物，从而通过阻断谷氨酰胺代谢增加活性氧。化合物在A549细胞异种移植模型中也表现出优异的抗增殖活性。我们进一步证明是一种安全的GAC变构抑制剂。提出了一个碱性亚口袋，这可能为未来新型GAC抑制剂的开发提供新策略。
