Development of Hsp90 beta-selective inhibitors as safer anti-cancer agents

开发 Hsp90 β 选择性抑制剂作为更安全的抗癌药物

基本信息

批准号：
9908341
负责人：
Sanket Mishra
金额：
$ 23.32万
依托单位：
GRANNUS THERAPEUTICS LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9908341
关键词：
Address Affinity Animal Model Antineoplastic Agents Binding Binding Sites Biological Assay Breast Adenocarcinoma Cancer cell line Cardiotoxicity Cell Line Cell Proliferation Client Clinical Clinical Trials Colon Adenocarcinoma Crystallization Data Dependence Development Dose Drug Design Drug Kinetics Exhibits Formulation Frequencies Funding Goals HSP 90 inhibition Heat shock proteins Heat-Shock Response Hepatotoxicity In Vitro Individual Investigational Drugs Investigational New Drug Application Lead Malignant Neoplasms Maximum Tolerated Dose Medical Metabolic Methods Molecular Chaperones Molecular Conformation N-terminal Oncogenic Pathway interactions Patients Peripheral Nervous System Diseases Pharmaceutical Preparations Phase Property Protein Inhibition Protein Isoforms Proteins Reporting Research Safety Schedule Series Signal Transduction Small Business Innovation Research Grant Structure Technology Therapeutic Time Toxic effect Toxicology Universities Work Xenograft procedure analog anti-cancer therapeutic antitumor agent base cancer therapy cancer type clinical candidate combinatorial design drug candidate drug development functional group improved in vivo inhibitor/antagonist lead optimization leukemia nanomolar novel preclinical study protein degradation protein folding research clinical testing side effect small molecule inhibitor translational study tumor progression

Address Affinity Animal Model Antineoplastic Agents Binding Binding Sites Biological Assay Breast Adenocarcinoma Cancer cell line Cardiotoxicity Cell Line Cell Proliferation Client Clinical Clinical Trials Colon Adenocarcinoma Crystallization Data Dependence Development Dose Drug Design Drug Kinetics Exhibits Formulation Frequencies Funding Goals HSP 90 inhibition Heat shock proteins Heat-Shock Response Hepatotoxicity In Vitro Individual Investigational Drugs Investigational New Drug Application Lead Malignant Neoplasms Maximum Tolerated Dose Medical Metabolic Methods Molecular Chaperones Molecular Conformation N-terminal Oncogenic Pathway interactions Patients Peripheral Nervous System Diseases Pharmaceutical Preparations Phase Property Protein Inhibition Protein Isoforms Proteins Reporting Research Safety Schedule Series Signal Transduction Small Business Innovation Research Grant Structure Technology Therapeutic Time Toxic effect Toxicology Universities Work Xenograft procedure analog anti-cancer therapeutic antitumor agent base cancer therapy cancer type clinical candidate combinatorial design drug candidate drug development functional group improved in vivo inhibitor/antagonist lead optimization leukemia nanomolar novel preclinical study protein degradation protein folding research clinical testing side effect small molecule inhibitor translational study tumor progression

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项目摘要

Abstract The 90 kD heat shock proteins (Hsp90) are molecular chaperones that are responsible for the folding of select proteins, many of which are directly associated with cancer progression. Consequently, inhibition of the Hsp90 protein folding machinery results in a combinatorial attack on numerous oncogenic pathways. Seventeen small molecule inhibitors of Hsp90 have entered clinical trials for the treatment of cancer, all of which bind the Hsp90 N-terminus and exhibit pan-inhibitory activity against all four Hsp90 isoforms. Pan-Inhibition of Hsp90 appears to be detrimental as toxicities have been reported alongside induction of the pro-survival heat shock response. The development of Hsp90 isoform-selective inhibitors represents an alternative approach towards the treatment of cancer and may reduce side effects observed with pan-Hsp90 inhibition. This application proposes optimization of a novel class of Hsp90β-selective inhibitors that induces the degradation of select Hsp90 clients without simultaneous induction of Hsp90 levels. Preliminary work involving Hsp90β-selective compounds at University of Notre Dame has established that Hsp90β inhibition offers a targeted and safer therapeutic approach for the treatment of cancer. In this Phase I, PrevAllergy (d/b/a Grannus Therapeutics) will optimize the efficacy and drug like properties of the novel Hsp90β-selective inhibitor using a rational, structure- based drug design approach to obtain a lead compound. Aim 1. Optimize the current lead Hsp90β-selective compounds by synthesizing rationally designed new analogs to improve affinity, pharmacokinetic properties and metabolic stability of the discovered series of Hsp90β-selective inhibitors. The working hypothesis is that introduction of functional groups will increase drug-likeness of our current lead compounds. Aim 2. Evaluate Hsp90β-selective inhibitors developed in Aim 1 utilizing pharmacokinetic assays and in vitro cellular studies, and in vivo studies to assist in the identification of a drug candidate. Based on the team's preliminary cellular studies involving multiple cancer cell lines, cancers with increased dependency upon Hsp90β have been identified, animal models of these identified cancer will be treated. Upon completion of the proposed work, Grannus Therapeutics will have identified lead compounds with improved drug-like properties to progress into Investigational New Drug (IND)-enabling studies. The result from Phase II will lead to an IND application and subsequent initiation of clinical trials to treat the identified cancers that still represent an unmet medical need. !

抽象的 90 kD热休克蛋白（HSP90）是分子伴侣，负责折叠选择蛋白质，其中许多与癌症进展直接相关。因此，抑制HSP90 蛋白质折叠机械导致对众多致癌途径的组合攻击。十七小 HSP90的分子抑制剂已进入癌症治疗的临床试验，所有这些都结合了HSP90 N末端和针对所有四个HSP90同工型的泛抑制活性。出现了HSP90的泛抑制作用据报道，毒性是有害的，同时又是促阳性热休克反应的诱导。 HSP90同工型选择性抑制剂的开发是一种替代方法治疗癌症，并可能减少PAN-HSP90抑制作用观察到的副作用。此应用程序提案优化一种新型的HSP90β选择性抑制剂，影响选择的降解 HSP90客户端没有同时诱导HSP90级别的客户。初步工作涉及HSP90β选择性巴黎圣母大学的化合物已经确定，HSP90β抑制可提供针对性，更安全的治疗癌症的治疗方法。在这一第一阶段，Profallergy（D/B/A Grannus Therapeutics）将优化新型HSP90β选择抑制剂的效率和药物，使用有理结构 - 获得铅化合物的基于药物设计方法。 AIM 1。优化当前的铅HSP90β选择性通过合成理性设计的新类似物来提高亲和力，药代动力学特性，化合物以及发现的HSP90β选择性抑制剂的代谢稳定性。工作的假设是官能团的引入将增加我们当前铅化合物的药物类似。目标2。评估 HSP90β选择性抑制剂在AIM 1中开发了使用药代动力学测定和体外细胞研究，和体内研究，以帮助鉴定候选药物。根据团队的初步蜂窝研究涉及多个癌细胞系，对HSP90β的依赖性增加的癌症已经是确定的，这些鉴定出的癌症的动物模型将得到治疗。拟议的工作完成后， Grannus Therapeutics将确定具有改善类似药物的特性的铅化合物，以发展为研究新药（IND）增强研究。第二阶段的结果将导致IND应用程序，并且随后开始临床试验，以治疗仍然代表未满足医疗需求的确定的癌症。呢