Profile substrates and inhibitors of protein lysine methyltransferase

蛋白质赖氨酸甲基转移酶的底物和抑制剂概况

• 批准号: 8414845
• 负责人: Minkui Luo
• 金额: $ 33.14万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8414845
• 关键词: Address; Affect; Apoptosis; Binding; Biological Assay; Biological Process; Cancer Diagnostics; Cancerous; Cell Proliferation; Cells; Chromosomes; DNA Double Strand Break; Data; Development; Disease; Engineering; Enzymes; Epigenetic Process; Goals; Histone H4; Histone-Lysine N-Methyltransferase; Histones; Intervention; Investigation; Label; Light; Link; Lysine; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Methionine; Methods; Methylation; Methyltransferase; Modification; Outcome; Pathologic Processes; Pathway interactions; Physiological Processes; Post-Translational Protein Processing; Process; Proliferating; Protein Methyltransferases; Protein p53; Proteins; Radiation; Radiation therapy; Reaction; Reagent; Regulation; Reporter; Reporting; Resistance; Role; Specificity; Structure; Technology; Therapeutic; Therapeutic Effect; Time; Work; analog; anticancer research; cancer cell; cancer diagnosis; cancer therapy; chemical group; cofactor; high throughput screening; improved; inhibitor/antagonist; innovative technologies; methyl group; new technology; novel; novel strategies; public health relevance; scaffold; small molecule; tool

DESCRIPTION (provided by applicant): Protein methyltransferases orchestrate epigenetic pathways through diverse posttranslational methylation. The reaction is carried out by protein lysine methyltransferases (PKMTs) through transferring the methyl group of SAM (S-adenosyl-L- methionine) to specific lysine(s) of substrates. The errors in the process have been implicated in many cancers. Accumulated evidence indicated that epigenetic diversity requires PKMTs to methylate histones and nonhistone proteins. However, few tools are available to unambiguously profile the nonhistone targets of designated PKMTs, particularly in context of proliferating cancer cells. In addition, few PKMT inhibitors are available to disrupt PKMT functions. Such situations significantly hinder our capability to develop cancer-therapeutic strategies with the PKMTs as novel targets. Our long-term goal is to elucidate and manipulate the biological functions of PKMT for cancer diagnosis and treatment. The objective of this proposal is to develop novel technologies and apply them to identify protein targets and small-molecule inhibitors of a cancer-relevant PKMT. Knowing the targets of the PKMT will be a key step toward fully understanding the epigenetic functions of the PKMT. More importantly, the inhibitors of the PKMT can be examined for their cancer-therapeutic effects. To profile the targets of the PKMT, we envision that the enzyme can be engineered to utilize SAM analogue cofactors and thus label its targets with distinct chemical groups. The distinct modifications will then be recognized by respective reporters. Meanwhile, a novel high-throughput screening approach will be implemented to identify the inhibitors of the PKMT. The impact of our target-profiling and inhibitor-identifying methods is further strengthened by their general applicability to other PKMTs.

描述（由申请人提供）：蛋白质甲基转移酶通过不同的翻译后甲基化协调表观遗传途径。该反应是通过蛋白质赖氨酸甲基转移酶（PKMT）将SAM（S-腺苷-L-蛋氨酸）的甲基转移到底物的特定赖氨酸上来进行的。许多癌症都与这一过程中的错误有关。积累的证据表明表观遗传多样性需要 PKMT 来甲基化组蛋白和非组蛋白。然而，很少有工具可用于明确分析指定 PKMT 的非组蛋白靶点，特别是在癌细胞增殖的情况下。此外，很少有 PKMT 抑制剂可破坏 PKMT 功能。这种情况极大地阻碍了我们开发以 PKMT 作为新靶点的癌症治疗策略的能力。我们的长期目标是阐明和操纵 PKMT 在癌症诊断和治疗中的生物学功能。该提案的目标是开发新技术并将其应用于识别癌症相关 PKMT 的蛋白质靶点和小分子抑制剂。了解 PKMT 的靶点将是充分了解 PKMT 表观遗传功能的关键一步。更重要的是，可以检查 PKMT 抑制剂的癌症治疗效果。为了分析 PKMT 的靶标，我们设想该酶可以被设计为利用 SAM 类似物辅因子，从而用不同的化学基团标记其靶标。然后，不同的修改将被各自的报告者识别。同时，将采用一种新颖的高通量筛选方法来鉴定 PKMT 的抑制剂。我们的目标分析和抑制剂识别方法的影响因它们对其他 PKMT 的普遍适用性而得到进一步加强。