Selective Inhibition of HDAC6 in Cancer Therapy

描述（由申请人提供）：拟定研究的目的是表征组蛋白脱乙酰酶6（HDAC 6）的新型同工酶选择性抑制剂，以进行人体临床研究。在蛋白酶体抑制后，不溶性泛素化蛋白质的核周聚集体（称为“侵袭体”）积累并通过自噬降解。HDAC 6是介导泛素化蛋白、微管蛋白和动力蛋白运动复合物之间相互作用的胞质蛋白。攻击体形成的遗传研究已经证明了HDAC 6酶功能的需要。候选人最近的工作证明HDAC 6是多发性骨髓瘤的癌症靶点，这是一种蛋白质催化剂机制研究的模型系统。 尽管许多HDAC抑制剂目前正在早期临床开发中，但靶向HDAC 6的药物尚未实现。使用HDAC 6选择性工具化合物tubacin和蛋白酶体抑制剂bortezaline，申请人设计了一种新的抗癌策略，靶向在多发性骨髓瘤、胰腺癌和卵巢癌的临床前模型中具有活性的蛋白cataline。药理学缺陷限制了tubacin的治疗发展。申请人最近的研究已经产生了一类新的高效双功能HDAC 6抑制剂（BH 6 - 54 A和BH 6 -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疗效测试。该候选人是一名接受过肿瘤学和血液学临床培训的医生兼科学家。他已经完成了两年的化学生物学博士后研究，专注于配体发现，蛋白质降解和HDAC 6。他的长期目标是建立和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：Dana-Farber癌症研究所血液肿瘤部的Kenneth安德森博士和哈佛和麻省理工学院布罗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，并将为实验癌症疗法的发现和开发建立学术途径。

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.