Small-molecule degraders of STAT5

STAT5 的小分子降解剂

基本信息

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
项目类别：
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

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

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项目摘要

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5（STAT5）的换能器和激活因子是转录因子，已经是被认为是一个有吸引力的癌症治疗靶标。但是，成功针对STAT5 被证明是非常挑战的。近年来，诱导的蛋白质降解已成为针对那些传统的“不良”或困难的治疗靶标的有效策略。在此R01奖中，我们建议设计和开发STAT5的小分子降级器。我们的初步数据表明，我们设计的STAT5降级可能有可能以及有选择地诱导人类癌细胞和特征肿瘤组织中的STAT5降解体内，导致对STAT5功能的有效抑制。重要的是，我们最好的STAT5 DEGRADER是有效地抑制人类CML和AML细胞系的细胞生长，具有多动stat5 并且能够在耐受剂量的剂量仪表室中诱导小鼠的肿瘤消退。确定Stat5配体和降解器的共结晶结构与 STAT5为我们提供了稳固的结构基础，以进一步优化。我们的最终目标 R01奖是为了开发高潜力，选择性和优化的STAT5 DEGRADER 治疗人类CML，AML和其他类型的具有多活跃STAT5的人类癌症。到实现我们的目标，我们提出以下具体目标：目标1：基于结构的设计和新STAT5降级器的合成以进一步优化降解效力，选择性，药代动力学和体内效率。目标2：研究新STAT5的体外活性，特异性和作用机理使用含有不同水平的活化STAT5蛋白的人类癌细胞系的降解者。目标3：确定代谢稳定性，药代动力学，药效学和IN STAT5降解器在小鼠模型中及其在小鼠中的潜在毒性中的体内抗癌活性。据我们所知，我们的实验室是第一个开发Protac小分子的人 STAT5降级器。该项目成功执行，将带来一流的，高度优化的 STAT5小分子降解者降至先进的临床前开发和临床试验作为一种新的治疗人类癌症患有活性STAT5的疗法。