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