Small-molecule STAT3 degraders

小分子 STAT3 降解剂

基本信息

批准号：
10066330
负责人：
SHAOMENG WANG
金额：
$ 62.01万
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：
2019
资助国家：
美国
起止时间：
2019-12-06 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10066330
关键词：
Address Affinity Antibodies Antineoplastic Agents Antisense Oligonucleotides Award Cancer cell line Cell Line Cell Nucleus Cell Survival Clinical Clinical Trials Complex Crystallization Data Development Dimerization Dose Down-Regulation Drug Kinetics Drug Targeting Drug resistance Evaluation Genes Genetic Transcription Goals Growth Growth Factor Human Immune Evasion In Vitro Investigation Laboratories Lead Leukemic Cell Lymphoma cell Malignant Neoplasms Mediating Medicine Metabolic Mus Neoplasm Metastasis Oncogenic Performance Pharmaceutical Preparations Pharmacodynamics Phosphorylation Play Prognosis Protac Protein Family Proteins Proteomics Reporting Role STAT protein STAT1 gene Schedule Signal Transduction Solid Stat3 protein Stat5 protein Structure Technology Testing Therapeutic Time Tissues Toxic effect Transactivation Tumor Tissue Xenograft Model Xenograft procedure angiogenesis anticancer activity base cancer cell cancer therapy cell growth clinical development cytokine design dimer early phase clinical trial human cancer mouse model human disease in vitro activity in vivo inhibitor/antagonist intravenous administration member neoplastic cell novel therapeutic intervention novel therapeutics preclinical development protein degradation response screening small molecule small molecule inhibitor therapeutic target therapy development transcription factor tumor tumor initiation tumor xenograft

项目摘要

Signal transducers and activator of transcription 3 (STAT3) is frequently activated in human cancers and aberrant activation of STAT3 signaling is involved in tumor initiation, progression, drug resistance and immune evasion. Thus, STAT3 has been considered to be a highly attractive cancer therapeutic target. However, discovery and development of highly potent and selective small-molecule inhibitors of STAT3 have proven to be very challenging for a number of reasons. The proteolysis targeting chimera (PROTAC) strategy has recently gained tremendous momentum for its promise for the discovery and development of an entirely different type of new therapeutics through inducing targeted protein degradation. We hypothesize that PROTAC STAT3 degraders (hereafter called STAT3 degraders) may be much more effective than STAT3 inhibitors in inhibition of STAT3 transcriptional activity. To date, no STAT3 degraders have been reported. Based upon a class of highly potent STAT3 inhibitors, we have designed and developed the first-in-class STAT3 degraders, as exemplified by our lead compound SD-36. SD-36 is highly potent and effective in inducing the degradation of STAT3 protein and demonstrates an absolute selectivity over other STAT members and all other >5,000 proteins examined. Degradation of STAT3 by SD-36 results in a robust suppression of STAT3 transcription activity and down-regulation of STAT3 transcription network in tumor cells. Our initial screening demonstrated that SD-36 inhibits the growth of a subset of AML and ALCL cell lines that express high levels of p-STAT3 (Y705). Our pharmacodynamic (PD) studies showed that a single intravenous administration of SD-36 is capable of reducing STAT3 protein by >90%, with the effect persisted for more than 3 days. SD-36 achieves complete tumor regression in multiple xenograft models in mice at well tolerate doss-schedules. Our data demonstrate that degradation of STAT3 protein is a highly promising cancer therapeutic strategy. Based upon our compelling preliminary data, we propose to design, synthesize and develop highly potent small-molecule STAT3 degraders as a new class of therapies for the treatment of human cancer and to elucidate their mechanism of action. In addition to performance of extensive evaluations of SD-36 in vitro and in vivo, we will further optimize SD-36 for potency and efficacy and address any weaknesses we uncover for SD-36. Our goal is to select one or more highly potent and optimized STAT3 degrader for advanced preclinical development for the treatment of human cancers with activated STAT3.

转录3（STAT3）的信号换能器和激活因子在人类癌症中经常被激活 STAT3信号传导的异常激活参与肿瘤的启动，进展，耐药性和免疫力逃避。因此，STAT3被认为是极具吸引力的癌症治疗靶标。然而，发现和开发STAT3的高度有效和选择性的小分子抑制剂已被证明出于多种原因要具有挑战性。靶向嵌合体（Protac）策略的蛋白水解最近已经获得了巨大的动力通过诱导发现和开发完全不同类型的新疗法的承诺靶向蛋白质降解。我们假设Protac Stat3降解器（以下称为STAT3 降解器）在抑制STAT3转录活性方面可能比STAT3抑制剂更有效。迄今为止，尚未报告STAT3降解器。基于一类高效的STAT3抑制剂，我们设计并开发了第一类 STAT3 DEGRADERS，以我们的铅化合物SD-36为例。 SD-36在高度有效和有效诱导STAT3蛋白的降解并证明与其他Stat的绝对选择性成员和所有其他> 5,000种蛋白质。 SD-36对STAT3的降解会导致强大 STAT3转录活性的抑制和肿瘤中STAT3转录网络的下调细胞。我们的初始筛选表明SD-36抑制了AML和ALCL细胞系的一部分的生长表达高水平的P-Stat3（Y705）。我们的药效学（PD）研究表明 SD-36的静脉内给药能够将STAT3蛋白降低> 90％，效果持续超过3天。 SD-36在小鼠的多个异种移植模型中实现了完全的肿瘤回归容忍陶器。我们的数据表明，STAT3蛋白的降解是一种非常有前途的癌症治疗策略。根据我们引人注目的初步数据，我们建议设计，合成和发展高度有效小分子STAT3降解器作为治疗人类癌症和疗法的新疗法阐明其作用机理。除了对体外SD-36的广泛评估以及在体内，我们将进一步优化SD-36的效力和功效，并解决我们发现的任何弱点 SD-36。我们的目标是为Advanced选择一个或多个高度有效且优化的STAT3 DEGRADER 临床前开发用于治疗具有活化STAT3的人类癌症。