Selective Inhibition of HDAC6 in Cancer Therapy

癌症治疗中 HDAC6 的选择性抑制

基本信息

批准号：
7841867
负责人：
JAMES E BRADNER
金额：
$ 13.93万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7841867
关键词：
Acetylation Affinity Animal Model Autophagocytosis Award Binding Biochemical Biological Biological Models Biology Bortezomib Cancer Biology Catabolism Cell Survival Cells Chemicals Clinical Clinical Trials Complex Credentialing Dana-Farber Cancer Institute Data Deacetylase Development Development Plans Drug Delivery Systems Dynein ATPase Enzymes Genetic Goals Heat shock proteins Hematology Histone Deacetylase Inhibitor Human In Vitro Institutes Investigation Isoenzymes Laboratories Laboratory Research Lead Ligand Binding Ligands Malignant - descriptor Malignant Neoplasms Malignant neoplasm of ovary Measurement Mediating Medical Oncology Mentors Modeling Motor Multiple Myeloma Mus Neoplasms Pancreas Pathway interactions Pharmaceutical Chemistry Phase Physicians Postdoctoral Fellow Pre-Clinical Model Preclinical Drug Development Property Proteasome Inhibition Proteasome Inhibitor Protein Biosynthesis Proteins Reagent Recombinants Research Research Personnel Research Proposals Response Elements Rodent Role Sampling Scientist Specificity Structure Testing Therapeutic Toxicology Training Translational Research Translations Tubulin Vorinostat Work cancer therapy cancer type chemical genetics clinically relevant comparative cytotoxic efficacy testing experience histone deacetylase 6 in vivo inhibitor/antagonist instrument molecular recognition mutant novel novel strategies pre-clinical research programs protein aggregate protein degradation protein misfolding research study stress protein therapeutic development therapeutic target tool tubacin

项目摘要

DESCRIPTION (provided by applicant): The goal of the proposed research is to characterize novel isoenzyme-selective inhibitors of histone deacetylase 6 (HDAC6) to enable human clinical investigation. Following proteasome inhibition, perinuclear aggregates of insoluble ubiquitinated proteins (termed 'aggresomes') accumulate and are degraded by autophagy. HDAC6 is a cytosolic protein mediating interactions between ubiquitinated proteins, alphatubulin and the dynein motor complex. Genetic studies of aggresome formation have demonstrated a requirement for HDAC6 enzyme function. Recent work by the candidate has credentialed HDAC6 as a cancer target in multiple myeloma, a model system for mechanistic studies of protein catabolism. Though many HDAC inhibitors are presently being prosecuted in early phase clinical development, drugs targeting HDAC6 have not been realized. Using the HDAC6-selective tool compound, tubacin, and the proteasome inhibitor, bortezomib, the applicant devised a novel anticancer strategy targeting protein catabolism with activity in preclinical models of multiple myeloma, pancreatic and ovarian cancer. Pharmacologic liabilities limit the therapeutic development of tubacin. Recent research by the applicant has resulted in a new class of highly potent bifunctional HDAC6 inhibitors (BH6-54A and BH6-1584). This research proposal outlines a biochemical study of bivalent molecular recognition and a late-phase preclinical drug development plan: in vitro toxicology, pharmacologic studies in rodents and efficacy testing in murine models of multiple myeloma. The candidate is a physician-scientist with clinical training in medical oncology and hematology. He has completed two years of post-doctoral research in chemical biology focusing on ligand discovery, protein degradation and HDAC6. His long-term goal is to establish and direct an academic research laboratory applying novel strategies in chemical biology to clinically-relevant challenges in malignant hematology. The proposed research will be carried out under the sponsorship of two mentors: Dr. Kenneth Anderson in the Division of Hematologic Neoplasia of the Dana-Farber Cancer Institute and Dr. Stuart Schreiber in the Chemical Biology Program of the Broad Institute of Harvard and MIT. This award will support a unique training experience in translational research and chemical biology, and will establish an academic pathway for the discovery and development of experimental cancer therapeutics.

描述（由申请人提供）：拟议研究的目标是表征组蛋白脱乙酰酶 6 (HDAC6) 的新型同工酶选择性抑制剂，以实现人类临床研究。蛋白酶体抑制后，不溶性泛素化蛋白的核周聚集体（称为“聚集体”）积累并被自噬降解。 HDAC6 是一种胞质蛋白，介导泛素化蛋白、α微管蛋白和动力蛋白运动复合体之间的相互作用。聚集体形成的遗传学研究已证明 HDAC6 酶功能是必需的。该候选人最近的工作已证明 HDAC6 是多发性骨髓瘤的癌症靶标，多发性骨髓瘤是蛋白质分解代谢机制研究的模型系统。尽管许多 HDAC 抑制剂目前正处于早期临床开发阶段，但针对 HDAC6 的药物尚未实现。使用HDAC6选择性工具化合物tubacin和蛋白酶体抑制剂bortezomib，申请人设计了一种针对蛋白质分解代谢的新型抗癌策略，在多发性骨髓瘤、胰腺癌和卵巢癌的临床前模型中具有活性。药理作用限制了tubacin 的治疗发展。申请人最近的研究产生了一类新的高效双功能HDAC6抑制剂（BH6-54A和BH6-1584）。该研究计划概述了二价分子识别的生化研究和后期临床前药物开发计划：体外毒理学、啮齿动物药理学研究和多发性骨髓瘤小鼠模型的功效测试。候选人是一位接受过肿瘤内科和血液学临床培训的医师科学家。他已经完成了两年的化学生物学博士后研究，重点关注配体发现、蛋白质降解和 HDAC6。他的长期目标是建立并指导一个学术研究实验室，将化学生物学的新策略应用于恶性血液学的临床相关挑战。拟议的研究将在两位导师的赞助下进行：达纳法伯癌症研究所血液肿瘤科的 Kenneth Anderson 博士和哈佛大学和麻省理工学院博德研究所化学生物学项目的 Stuart Schreiber 博士。该奖项将支持转化研究和化学生物学方面的独特培训经验，并将为实验性癌症疗法的发现和开发建立学术途径。