Harnessing PHGDH Inhibition for Cancer Therapy: Mechanisms, SAR, Computational Aspects, and Clinical Potential

3-Phosphoglycerate dehydrogenase (PHGDH) is a key enzyme in the serine biosynthesis pathway, supporting cancer cell growth, survival, and proliferation. Its overexpression is frequently observed in aggressive cancers such as breast cancer, melanoma, and glioma, where it drives tumor growth, metastasis, and resistance to oxidative stress. Targeting PHGDH with small-molecule inhibitors has emerged as a promising therapeutic strategy. Notable inhibitors like NCT-503, CBR-5884, Azacoccone E, and Ixocarpalactone A, along with covalent inhibitors such as Withangulatin A, exhibit potent anticancer activity by limiting serine availability and inducing apoptosis. Gene-silencing techniques, including RNA interference (RNAi) and CRISPR/Cas9, further validate PHGDH as a therapeutic target. Advances in computational methods and structure-activity relationship (SAR) analysis have accelerated the discovery of selective PHGDH inhibitors, offering insights into binding mechanisms and facilitating rational drug design. However, cancer cells can activate alternative metabolic pathways, such as glutaminolysis, to evade PHGDH inhibition. Thus, combination therapies targeting multiple metabolic nodes are being explored to enhance efficacy and overcome resistance. Ongoing research focuses on optimizing PHGDH inhibitors through virtual screening, QSAR modeling, and clinical trials, aiming to integrate them into precision oncology and develop effective therapies for patients with high PHGDH expression or specific metabolic profiles.