Small-molecule STAT3 degraders

小分子 STAT3 降解剂

• 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
• 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

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.

信号转导和转录激活因子3 （STAT3）在人类癌症和肿瘤中经常被激活