Small-molecule degraders of STAT5

STAT5 的小分子降解剂

• 批准号: 10718129
• 负责人: SHAOMENG WANG
• 金额: $ 64.7万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718129
• 关键词: Acute Myelocytic Leukemia; Acute T Cell Leukemia; Acute leukemia; Affinity; Award; Binding; Cancer cell line; Cell Line; Cells; Charge; Chronic; Clinical Trials; Complex; Data; Development; Dimerization; Dose; Drug Kinetics; Genetic Transcription; Goals; Hematopoietic; Homo; Human; Hyperactivity; Investigation; Janus kinase; Laboratories; Ligands; Lymphoma; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metabolic; Mus; Mutate; Permeability; Pharmacodynamics; Phosphorylation; Phosphotransferases; Phosphotyrosine; Protac; Protein Degradation Induction; Proteins; Reporting; STAT protein; STAT3 gene; STAT5B gene; STAT6 gene; Schedule; Sequence Homology; Signal Induction; Solid; Specificity; Structure; T-Cell Prolymphocytic Leukemia; T-Lymphocyte; Technology; Therapeutic; Therapeutic Agents; Toxic effect; Transcription Coactivator; Transducers; Tumor Tissue; Xenograft Model; anticancer activity; cancer cell; cancer therapy; cell growth; design; gain of function mutation; in vitro activity; in vivo; inhibitor; melanoma; member; mouse model; novel therapeutic intervention; novel therapeutics; preclinical development; small molecule; small molecule inhibitor; src Homology Domains; therapeutic target; transcription factor; tumor; tumor progression; tumor xenograft

Abstract Transducer and Activator of Transcription 5 (STAT5) is a transcriptional factor and has been proposed as an attractive cancer therapeutic target. However, successful of targeting STAT5 has proven to be very challenging. In recent years, induced protein degradation has emerged as an effective strategy for targeting those traditional “undruggable” or difficult therapeutic targets. In this R01 award, we propose to design and develop small-molecule degraders of STAT5. Our preliminary data have demonstrated that our designed STAT5 degraders potently and selectively induce STAT5 degradation in human cancer cells and in xenograft tumor tissue in vivo, leading to effective inhibition of STAT5 function. Importantly, our best STAT5 degrader is effective in inhibition of cell growth in human CML and AML cell lines with hyperactive STAT5 and is capable of inducing tumor regression in mice at well tolerated dose-schedules. Determination of co-crystal structures of both STAT5 ligands and degraders in complex with STAT5 provides us with a solid structural basis for further optimization. Our ultimate goal of this R01 award is to develop a highly potent, selective, and optimized STAT5 degrader for the treatment of human CML, AML and other types of human cancers with hyperactive STAT5. To achieve our goal, we propose to the following specific Aims: Aim 1: Structure-based design and synthesis of new STAT5 degraders to further optimize degradation potency, selectivity, pharmacokinetics, and in vivo efficacy. Aim 2: Investigation of the in vitro activity, specificity, and mechanism of action of new STAT5 degraders using human cancer cell lines containing different levels of activated STAT5 protein. Aim 3: Determination of the metabolic stability, pharmacokinetics, pharmacodynamics, and in vivo anticancer activity of STAT5 degraders in mouse models and their potential toxicity in mice. To the best of our knowledge, our laboratory is the first to develop PROTAC small-molecule STAT5 degraders. Successfully performed, this project will bring a first-in-class, highly optimized STAT5 small-molecule degrader into advanced preclinical development and clinical trials as a new therapy for the treatment of human cancers with activated STAT5.

摘要 转录因子和转录激活子5（STAT5）是一种转录因子， 作为一个有吸引力的癌症治疗靶点。然而，成功靶向STAT5 已经证明是非常具有挑战性的。近年来，诱导蛋白质降解已经出现， 一种有效的策略，针对那些传统的“不可药”或困难的治疗目标。 在这个R01奖项中，我们建议设计和开发STAT 5的小分子降解剂。我们 初步数据表明，我们设计的STAT5降解剂有效， 选择性诱导人癌细胞和异种移植肿瘤组织中的STAT5降解， 体内，导致STAT5功能的有效抑制。重要的是，我们最好的STAT5降解剂是 有效抑制具有过度活跃的STAT5的人CML和AML细胞系中的细胞生长 并且能够在耐受良好的剂量方案下诱导小鼠肿瘤消退。 STAT5配体和降解物与以下物质复合的共晶体结构的测定 STAT5为进一步优化提供了坚实的结构基础。我们的最终目标是 R01奖是开发一种高效，选择性和优化的STAT5降解剂， 治疗人CML、AML和具有过度活跃的STAT5的其他类型的人癌症。到 为了实现我们的目标，我们提出以下具体目标： 目的1：基于结构设计和合成新的STAT5降解剂，以进一步优化 降解效力、选择性、药代动力学和体内功效。 目的2：研究新STAT5的体外活性、特异性和作用机制 使用含有不同水平的活化的STAT5蛋白的人癌细胞系的降解剂。 目的3：测定代谢稳定性、药代动力学、药效学和体内代谢 STAT5降解物在小鼠模型中的体内抗癌活性及其在小鼠中的潜在毒性。 据我们所知，我们的实验室是第一个开发PROTAC小分子 STAT5降解剂。成功执行，该项目将带来一流的，高度优化的 STAT5小分子降解剂进入高级临床前开发和临床试验， 用于治疗具有活化的STAT5的人类癌症的新疗法。