权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Engineering the Next Generation of Safer Hsp90 Inhibitors

设计下一代更安全的 Hsp90 抑制剂

基本信息

批准号：
10587304
负责人：
Brian S J Blagg
金额：
$ 46.33万
依托单位：
UNIVERSITY OF NOTRE DAME
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：
2023-03-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10587304
关键词：
3-Dimensional Ablation Academia Affinity Aftercare Apoptosis Apoptotic Binding Binding Sites Biological Markers C-terminal Cell Line Cells Cetuximab Cisplatin Client Clinic Clinical Trials Development Dose Dose Limiting Drug Industry Drug Kinetics Drug resistance Drug toxicity Engineering Enzymes Exhibits Geldanamycin Genes Growth HSP 90 inhibition Head and Neck Squamous Cell Carcinoma Heat-Shock Response Hepatotoxicity Immune Lead Ligands Malignant - descriptor Malignant Neoplasms Mediating Modification Molecular Chaperones Molecular Conformation N-terminal Non-Malignant Novobiocin Pathway interactions Patients Pharmaceutical Preparations Population Pre-Clinical Model Process Proliferating Proteins Research Personnel Resistance Schedule Seminal Series Signal Transduction Signaling Protein Solubility Structure Therapeutic Toxic effect analog anti-cancer anticancer activity antitumor drug cancer cell cancer therapy clinical development improved in vivo in vivo evaluation inhibitor innovation lead optimization meter molecular recognition nanomolar neoplastic cell next generation novel novel anticancer drug novel strategies polypeptide pre-IND studies predictive modeling prevent process optimization protein degradation protein folding research clinical testing segregation single-cell RNA sequencing small molecule small molecule inhibitor therapeutic target transcriptome sequencing tumor tumor growth tumorigenic

项目摘要

Summary: Hsp90 is a molecular chaperone that is responsible for the conformational maturation of signaling proteins associated with all ten hallmarks of cancer, making it a promising target for the treatment of cancer, as multiple signaling nodes can be simultaneously derailed as a consequence of Hsp90 inhibition. Moreover, researchers have shown that Hsp90 inhibitors accumulate in tumors with high differential selectivity, making Hsp90 a highly sought after target for cancer. Unfortunately, clinical trials with 17 small molecule inhibitors have led to multiple detriments that have significantly dampened enthusiasm for Hsp90 inhibitors, as increased levels of Hsp90 were observed in the clinic, which led to dose-escalating toxicities among other concerns. Consequently, Hsp90 remains a desirable target for the development of cancer chemotherapeutics, but new approaches to inhibit the protein machinery are needed that do not induce Hsp90 levels. Through a number of seminal studies, it has been shown that inhibitors of the Hsp90 C-terminal domain can segregate Hsp90 inhibition from induction of Hsp90 levels, and therefore, we propose in this application to optimize these compounds and to perform a number of pre-IND studies on the best molecules in an effort to move them toward clinical evaluation.

总结：热休克蛋白90是一种分子伴侣，负责构象成熟，与癌症的所有十个标志相关的信号蛋白，使其成为一个有前途的作为治疗癌症的靶点，多个信号传导节点可以同时由于Hsp 90抑制而脱轨。此外，研究人员已经表明， Hsp 90抑制剂以高差异选择性在肿瘤中积累，使Hsp 90成为一种免疫抑制剂。是癌症治疗的热门目标不幸的是，17个小分子的临床试验抑制剂导致了多项措施，大大挫伤了人们的热情，对于Hsp 90抑制剂，由于在临床中观察到Hsp 90水平增加，剂量递增的毒性以及其他问题。因此，Hsp 90仍然是一种癌症化疗药物开发的理想目标，但新方法需要不诱导Hsp 90水平的蛋白质机器来抑制。通过大量开创性的研究表明，Hsp 90 C-末端的抑制剂结构域可以将Hsp 90抑制与Hsp 90水平的诱导分离，因此，在本申请中，我们提出优化这些化合物并进行许多对最好的分子进行IND前研究，努力将其推向临床评价