ArticleBioorganic & medicinal chemistry2018
Discovery and optimization of piperazine-1-thiourea-based human phosphoglycerate dehydrogenase inhibitors.
Article in Bioorganic & medicinal chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 44 citations in OpenAlex.
- Integrating AI in Medicinal Chemistry for Accelerated Drug Discovery: A Comprehensive SAR (CSAR) Optimization Strategy and Discovery of Potent ALDH3A1 Inhibitors.Journal of medicinal chemistry · 2026Article
- Review
- Article
- Synthesis and Elaboration of Medium-Sized Ring Building Blocks Prepared via Cascade Ring Expansion Reactions.The Journal of organic chemistry · 2025Article
- The Inhibitory Effects of NCT503 and Exogenous Serine on High-Selenium Induced Insulin Resistance in Mice.Nutrients · 2025Article
- PHGDH Induction by MAPK Is Essential for Melanoma Formation and Creates an Actionable Metabolic Vulnerability.Cancer research · 2025Article
- Cyproheptadine inhibits in vitro and in vivo lung metastasis and drives metabolic rewiring.Molecular biology reports · 2024Article
- Thioamides in medicinal chemistry and as small molecule therapeutic agents.European journal of medicinal chemistry · 2024Review
- Molecular glue triggers degradation of PHGDH by enhancing the interaction between DDB1 and PHGDH.Acta pharmaceutica Sinica. B · 2024Article
- MAPK-mediated PHGDH induction is essential for melanoma formation and represents an actionable vulnerability.bioRxiv : the preprint server for biology · 2024Article
- Identification of novel PHGDH inhibitors based on computational investigation: an all-in-one combination strategy to develop potential anti-cancer candidates.Frontiers in pharmacology · 2024Article
- Metabolic control of cancer metastasis: role of amino acids at secondary organ sites.Oncogene · 2023Review
- Targeting cancer metabolism in the era of precision oncology.Nature reviews. Drug discovery · 2022Review
- Lineage-specific silencing of PSAT1 induces serine auxotrophy and sensitivity to dietary serine starvation in luminal breast tumors.Cell reports · 2022Article
- Targeting Serine in Cancer: Is Two Better Than One?Trends in cancer · 2021Article
- 3-Phosphoglycerate dehydrogenase: a potential target for cancer treatment.Cellular oncology (Dordrecht, Netherlands) · 2021Review
- Can small molecular inhibitors that stop de novo serine synthesis be used in cancer treatment?Cell death discovery · 2021Review
- EWS-FLI1-regulated Serine Synthesis and Exogenous Serine are Necessary for Ewing Sarcoma Cellular Proliferation and Tumor Growth.Molecular cancer therapeutics · 2020Article
- Chiral Thioureas-Preparation and Significance in Asymmetric Synthesis and Medicinal Chemistry.Molecules (Basel, Switzerland) · 2020Review
- Amino acids in cancer.Experimental & molecular medicine · 2020Review
Corrections and comments
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Authors and funding
15 authors at 2 institutions in 1 country.
Funding
Abstract
Proliferating cells, including cancer cells, obtain serine both exogenously and via the metabolism of glucose. By catalyzing the first, rate-limiting step in the synthesis of serine from glucose, phosphoglycerate dehydrogenase (PHGDH) controls flux through the biosynthetic pathway for this important amino acid and represents a putative target in oncology. To discover inhibitors of PHGDH, a coupled biochemical assay was developed and optimized to enable high-throughput screening for inhibitors of human PHGDH. Feedback inhibition was minimized by coupling PHGDH activity to two downstream enzymes (PSAT1 and PSPH), providing a marked improvement in enzymatic turnover. Further coupling of NADH to a diaphorase/resazurin system enabled a red-shifted detection readout, minimizing interference due to compound autofluorescence. With this protocol, over 400,000 small molecules were screened for PHGDH inhibition, and following hit validation and triage work, a piperazine-1-thiourea was identified. Following rounds of medicinal chemistry and SAR exploration, two probes (NCT-502 and NCT-503) were identified. These molecules demonstrated improved target activity and encouraging ADME properties, enabling in vitro assessment of the biological importance of PHGDH, and its role in the fate of serine in PHGDH-dependent cancer cells. This manuscript reports the assay development and medicinal chemistry leading to the development of NCT-502 and -503 reported in Pacold et al. (2016).
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.