Discovery of inhibitors of the metabolic oncogene 3-phosphoglycerate dehydrogenas

代谢癌基因 3-磷酸甘油酸脱氢酶抑制剂的发现

• 批准号: 8648321
• 负责人: Kellen Leonard Olszewski
• 金额: $ 17.21万
• 依托单位: KADMON CORPORATION, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-11 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8648321
• 关键词: 3-phosphoglycerate; Address; Adopted; Affinity; Animal Husbandry; Binding; Biological Assay; Breast Melanoma; Cancer cell line; Carbon; Cell Culture Techniques; Cell Line; Cells; Clinical; Computer Simulation; Data; Development; Doctor of Philosophy; Dose; Drug Kinetics; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzyme Tests; Enzymes; Exhibits; Genes; Genomics; Glycine; Goals; Growth; Housing; Human; In Vitro; Inhibitory Concentration 50; Investigation; Libraries; Lipids; Malignant Neoplasms; Maximum Tolerated Dose; Metabolic; Metabolism; Modality; Modeling; Mus; Normal tissue morphology; Nucleotide Biosynthesis; Oncogenes; Pathway interactions; Pharmacology; Phase; Phenotype; Phosphoglycerate dehydrogenase; Proteins; RNA Interference; Reaction; Research Infrastructure; Resistance; Serine; Site; Small Business Innovation Research Grant; Solid Neoplasm; Specificity; Structure; System; Technology; Testing; Therapeutic; Tumor Volume; Validation; Work; Xenograft Model; Xenograft procedure; base; cancer cell; cancer type; chemical synthesis; commercialization; design; drug discovery; folic acid metabolism; follow-up; human tissue; in vivo; inhibitor/antagonist; lipid biosynthesis; malignant breast neoplasm; meetings; metabolic abnormality assessment; metabolomics; novel; nucleotide metabolism; pre-clinical; public health relevance; research study; scaffold; screening; small molecule; small molecule libraries; therapeutic target; tissue culture; triple-negative invasive breast carcinoma

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：在实体瘤中描述了许多深刻的代谢改变，这些改变提供了有吸引力的治疗靶点。一种最近描述的“代谢癌基因”是3-磷酸甘油酸脱氢酶（PHGDH），其是合成丝氨酸和甘氨酸用于蛋白质、脂质、叶酸和核苷酸代谢的途径中的限速步骤。PHGDH基因在广泛的人类癌症中在基因组水平上扩增，并且特别与某些治疗抗性亚型相关，例如“三阴性”乳腺癌，其对新型、安全和有效的治疗提出了主要的未满足的临床需求。已经证明PHGDH敲低对培养物和异种移植模型中的PHGDH扩增的细胞系具有特异性毒性。然而，迄今为止，尚未描述哺乳动物PHGDH的特异性抑制剂，严重限制了对这种令人兴奋的新癌症靶点的研究。为了满足这一需求，Kadmon Corporation启动了一个项目，旨在发现和开发特定的PHGDH抑制剂，并通过代谢分析验证其作用机制。本项目建议：（1）双轨药物发现工作，包括针对一百万化合物小分子文库的纯化PHGDH的高通量亲和筛选，以及基于结合至其底物的PHGDH的晶体结构的基于片段的药物发现项目;（2）通过确认PHGDH-扩增系的特异性抑制和建立抑制剂代谢的系统水平定量模型来验证PHGDH抑制剂，处理细胞[;和（3）这些PHGDH抑制剂在乳腺癌的小鼠异种移植模型中的体内验证]。这些研究将共同产生第一个描述的特异性和细胞活性的人PHGDH抑制剂，这是I期SBIR的首要目标。SBIR II期的总体策略是优化一种或多种抑制剂的药理学，并完成必要的临床前实验，以实现IND申请。关于临床开发和商业化，最初的适应症将是用于治疗ER阴性乳腺癌和黑色素瘤。从长远来看，也有可能治疗已被证明扩增PHGDH的多种其他癌症。