Selective Inhibition of HDAC6 in Cancer Therapy

描述(由申请人提供)：拟议研究的目标是表征组蛋白脱乙酰基酶6(HDAC6)的新型同工酶选择性抑制剂，以便进行人类临床研究。在蛋白酶体被抑制之后，不溶性泛素化蛋白(称为侵袭体)在核周围聚集，并通过自噬被降解。HDAC6是一种胞浆蛋白，介导泛素化蛋白、Alphatubuin和动力蛋白运动复合体之间的相互作用。侵袭体形成的遗传学研究表明，HDAC6酶的功能是必需的。候选人最近的工作证明HDAC6是多发性骨髓瘤的癌症靶点，这是一种蛋白质分解代谢机制研究的模型系统。 虽然许多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，申请人设计了一种新的抗癌策略，针对多发性骨髓瘤、胰腺癌和卵巢癌临床前模型中具有活性的蛋白质分解代谢。药理上的缺陷限制了Tubacin的治疗发展。申请人最近的研究导致了一类新的高效双功能HDAC6抑制剂(BH6-54A和BH6-1584)。 这项研究计划概述了二价分子识别的生化研究和晚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。候选人是一名内科科学家，曾接受过内科肿瘤学和血液学方面的临床培训。他已经完成了两年的化学生物学博士后研究，重点是配体发现、蛋白质降解和HDAC6。他的长期目标是建立和指导一个学术研究实验室，应用化学生物学的新策略来应对恶性血液学的临床相关挑战。这项拟议的研究将在两位导师的赞助下进行：丹纳-法伯癌症研究所血液肿瘤部门的Kenneth Anderson博士和哈佛大学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。 该奖项将支持在翻译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发展建立一条学术道路。

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.