Many profound metabolic alterations have been described in solid tumors which present attractive therapeutic targets. One recently described 'metabolic oncogene' is 3- phosphoglycerate dehydrogenase (PHGDH), the rate-limiting step in the pathway synthesizing serine and glycine for proteins, lipids, folate and nucleotide metabolism. The PHGDH gene is amplified at the genomic level across a wide spectrum of human cancers, and is particularly associated with certain treatment-resistant subtypes, such as 'triple-negative' breast cancers, that present a major unmet clinical need for novel, safe and effective therapeutics. PHGDH knockdown has been demonstrated to be specifically toxic to PHGDH-amplified cell lines both in culture and in xenograft models. However, to date no specific inhibitors of mammalian PHGDH have yet been described, severely limiting investigation into this exciting new cancer target. To address this need Kadmon Corporation has initiated a project towards the discovery and development of specific PHGDH inhibitors, and the validation of their mechanism of action by metabolic profiling. This present project proposes: (1) a dual-track drug-discovery effort encompassing both high-throughput affinity screening of purified PHGDH against a one million- compound small molecule library, and a fragment-based drug discovery project based on the crystal structure of PHGDH bound to its substrates; (2) validation of PHGDH inhibitors by confirming specific inhibition of PHGDH-amplified lines and building systems-level quantitative models of the metabolism of inhibitor-treated cells[; and (3) i vivo validation of these PHGDH inhibitors in a mouse xenograft model of breast cancer]. Together these studies will produce the first described specific and cell-active inhibitors of human PHGDH, the overarching aim of this Phase I SBIR. The general strategy in SBIR Phase II will be to optimize the pharmacology of one or more inhibitor and to complete necessary preclinical experiments to enable IND filing. With respect to clinical development and commercialization, the initial indication will be for treatment of ER-negative breast cancers and melanomas. In the long term, there is the potential also to treat multiple other cancers that have been demonstrated to amplify PHGDH.
Thesaurus Terms: 3-Phosphoglycerate;Address;Adopted;Affinity;Animal Husbandry;Base;Binding (Molecular Function);Biological Assay;Breast Melanoma;Cancer Cell;Cancer Cell Line;Cancer Type;Carbon;Cell Culture Techniques;Cell Line;Cells;Chemical Synthesis;Clinical;Commercialization;Computer Simulation;Data;Design;Development;Doctor Of Philosophy;Dose;Drug Discovery;Drug Kinetics;Enzyme Inhibitor Drugs;Enzyme Inhibitors;Enzyme Tests;Enzymes;Exhibits;Folic Acid Metabolism;Follow-Up;Genes;Genomics;Glycine;Goals;Growth;Housing;Human;Human Tissue;In Vitro;In Vivo;Inhibitor/Antagonist;Inhibitory Concentration 50;Investigation;Libraries;Lipid Biosynthesis;Lipids;Malignant Breast Neoplasm;Malignant Neoplasms;Maximum Tolerated Dose;Meetings;Metabolic;Metabolic Abnormality Assessment;Metabolism;Metabolomics;Modality;Modeling;Mus;Normal Tissue Morphology;Novel;Nucleotide Biosynthesis;Nucleotide Metabolism;Oncogenes;Pathway Interactions;Pharmacology;Phase;Phenotype;Phosphoglycerate Dehydrogenase;Pre-Clinical;Proteins;Public Health Relevance;Reaction;Research Infrastructure;Research Study;Resistance;Rna Interference;Scaffold;Screening;Serine;Site;Small Business Innovation Research Grant;Small Molecule;Small Molecule Libraries;Solid Neoplasm;Specificity;Structure;System;Technology;Testing;Therapeutic;Therapeutic Target;Tissue Culture;Triple-Negative Invasive Breast Carcinoma;Tumor Volume;Validation;Work;Xenograft Model;Xenograft Procedure;
