Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Second Road, Shanghai 200025, China.
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
Bioorg Chem. 2020 Mar;96:103620. doi: 10.1016/j.bioorg.2020.103620. Epub 2020 Jan 25.
Glycolysis is enhanced in cancer cells. Cancer cells utilize glycolysis as their primary energy source, even under aerobic conditions. This is known as the Warburg effect. Thus, effective inhibition of the glycolytic pathway is a crucial component of cancer therapy. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an important enzyme in glycolysis and overexpresses in cancers. Therefore, targeting GAPDH to inhibit its role in glycolysis is important for GAPDH functional studies and the treatment of cancers. However, only a few GAPDH inhibitors have been reported. In our current study, we identified a GAPDH inhibitor, DC-5163, using docking-based virtual screening and biochemical and biophysical analysis. DC-5163 is a small molecule compound that inhibits GAPDH enzyme activity and cancer cell proliferation (normal cells were tolerant to it). It can inhibit glycolysis pathway partially, which was manifested by decreased glucose uptake and lactic acid production. And it also leaded to cell death through apoptotic pathways. This study reflects the pivotal role of GAPDH in cancer cells and demonstrates that DC-5163 is a useful inhibitor and can be of value in studying the role of GAPDH and the development of new clinical cancer treatments.
糖酵解在癌细胞中增强。癌细胞即使在有氧条件下也将糖酵解作为其主要能量来源，这被称为瓦博格效应。因此，有效抑制糖酵解途径是癌症治疗的关键组成部分。甘油醛-3-磷酸脱氢酶（GAPDH）是糖酵解中的一种重要酶，在癌症中过度表达。因此，靶向 GAPDH 以抑制其在糖酵解中的作用对于 GAPDH 功能研究和癌症治疗很重要。然而，仅报道了少数 GAPDH 抑制剂。在我们目前的研究中，我们使用基于对接的虚拟筛选和生化及生物物理分析鉴定了 GAPDH 抑制剂 DC-5163。DC-5163 是一种小分子化合物，可抑制 GAPDH 酶活性和癌细胞增殖（正常细胞对此具有耐受性）。它可以部分抑制糖酵解途径，表现为葡萄糖摄取和乳酸生成减少。并且它还通过凋亡途径导致细胞死亡。这项研究反映了 GAPDH 在癌细胞中的关键作用，并表明 DC-5163 是一种有用的抑制剂，可用于研究 GAPDH 的作用和开发新的临床癌症治疗方法。
