Wuya College of Innovation, School of Pharmacy, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China.
Cell Oncol (Dordr). 2021 Jun;44(3):541-556. doi: 10.1007/s13402-021-00599-9. Epub 2021 Mar 18.
Metabolic changes have been recognized as an important hallmark of cancer cells. Cancer cells can promote their own growth and proliferation through metabolic reprogramming. Particularly, serine metabolism has frequently been reported to be dysregulated in tumor cells. 3-Phosphoglycerate dehydrogenase (PHGDH) catalyzes the first step in the serine biosynthesis pathway and acts as a rate-limiting enzyme involved in metabolic reprogramming. PHGDH upregulation has been observed in many tumor types, and inhibition of PHGDH expression has been reported to inhibit the proliferation of PHGDH-overexpressing tumor cells, indicating that it may be utilized as a target for cancer treatment. Recently identified inhibitors targeting PHGDH have already shown effectiveness. A further in-depth analysis and concomitant development of PHGDH inhibitors will be of great value for the treatment of cancer.
In this review we describe in detail the role of PHGDH in various cancers and inhibitors that have recently been identified to highlight progression in cancer treatment. We also discuss the development of new drugs and treatment modalities based on PHGDH targets. Overexpression of PHGDH has been observed in melanoma, breast cancer, nasopharyngeal carcinoma, parathyroid adenoma, glioma, cervical cancer and others. PHGDH may serve as a molecular biomarker for the diagnosis, prognosis and treatment of these cancers. The design and development of novel PHGDH inhibitors may have broad implications for cancer treatment. Therapeutic strategies of PHGDH inhibitors in combination with traditional chemotherapeutic drugs may provide new perspectives for precision medicine and effective personalized treatment for cancer patients.
代谢变化已被认为是癌细胞的一个重要特征。癌细胞可以通过代谢重编程来促进自身的生长和增殖。特别是，丝氨酸代谢经常在肿瘤细胞中被报道失调。3-磷酸甘油酸脱氢酶（PHGDH）催化丝氨酸生物合成途径的第一步，作为代谢重编程中的限速酶起作用。PHGDH 在许多肿瘤类型中上调，并且抑制 PHGDH 表达已被报道抑制 PHGDH 过表达肿瘤细胞的增殖，表明它可能被用作癌症治疗的靶点。最近发现的针对 PHGDH 的抑制剂已经显示出有效性。对 PHGDH 抑制剂的进一步深入分析和伴随开发对于癌症治疗将具有重要价值。
在这篇综述中，我们详细描述了 PHGDH 在各种癌症中的作用以及最近发现的针对 PHGDH 的抑制剂，以突出癌症治疗的进展。我们还讨论了基于 PHGDH 靶点的新药和治疗方式的开发。PHGDH 在黑色素瘤、乳腺癌、鼻咽癌、甲状旁腺腺瘤、神经胶质瘤、宫颈癌等中过表达。PHGDH 可能作为这些癌症的诊断、预后和治疗的分子生物标志物。新型 PHGDH 抑制剂的设计和开发可能对癌症治疗具有广泛的意义。PHGDH 抑制剂与传统化疗药物联合的治疗策略可能为癌症患者的精准医学和有效个体化治疗提供新的视角。
