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.

抽象的 转录转导子和激活子 5 (STAT5) 是一种转录因子，已被 被认为是一个有吸引力的癌症治疗靶点。然而，成功靶向STAT5 事实证明这是非常具有挑战性的。近年来，诱导蛋白质降解已成为 针对那些传统的“无法成药”或困难的治疗目标的有效策略。 在本次R01奖中，我们建议设计和开发STAT5的小分子降解剂。我们的 初步数据表明，我们设计的 STAT5 降解剂有效且 在人类癌细胞和异种移植肿瘤组织中选择性诱导 STAT5 降解 体内，导致有效抑制 STAT5 功能。重要的是，我们最好的 STAT5 降解剂是 有效抑制具有高活性 STAT5 的人 CML 和 AML 细胞系的细胞生长 并且能够在耐受良好的剂量方案下诱导小鼠肿瘤消退。 测定 STAT5 配体和降解剂与复合物的共晶结构 STAT5为我们进一步优化提供了坚实的结构基础。我们的最终目标是 R01 奖旨在开发一种高效、选择性和优化的 STAT5 降解剂 使用高活性 STAT5 治疗人类 CML、AML 和其他类型的人类癌症。到 为了实现我们的目标，我们提出以下具体目标： 目标1：基于结构的设计和合成新的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。 目标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 STAT5 蛋白的人类癌细胞系的降解剂。 目标 3：测定代谢稳定性、药代动力学、药效学和 STAT5降解剂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小分子的实验室 STAT5 降解剂。如果该项目成功实施，将带来一流的、高度优化的 STAT5小分子降解剂进入先进的临床前开发和临床试验 利用激活的 STAT5 治疗人类癌症的新疗法。