Inducing Protein Degradation: A New Pharmaceutical Paradigm

诱导蛋白质降解：新的制药范例

• 批准号: 9142301
• 负责人: CRAIG M CREWS
• 金额: $ 89.35万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-09 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9142301
• 关键词: Academia; Address; Cell Culture Techniques; Chimera organism; Development; Disease; Drug Industry; Drug Targeting; Drug usage; FDA approved; Future; Genomics; Health; Multiple Myeloma; Nuclear Hormone Receptors; Oncogenes; Oncogenic; Pharmaceutical Preparations; Pharmacologic Substance; Play; Proteasome Inhibitor; Proteins; Proteolysis; Recruitment Activity; Refractory; Relapse; Research; Small Interfering RNA; Technology; Translating; anticancer research; base; bench to bedside; drug development; in vivo; innovation; knock-down; novel; novel anticancer drug; novel therapeutics; oncology; protein degradation; small molecule; success; transcription factor; ubiquitin-protein ligase; wasting

 DESCRIPTION (provided by applicant): The pharmaceutical industry is in a crisis; unfortunately the post-genomic era has not significantly changed the number of proteins pursued by drug companies. This dearth of new cancer drug targets has resulted in too many `me too' drugs and wasted effort. To address this need, my lab has focused on developing the new field of `Controlled Proteostasis'. Our initial efforts focused on inhibiting protein turnover; we developed a novel proteasome inhibitor, YU101, which served as the basis of a new oncology-based biopharma, Proteolix, Inc. from my lab. Ultimately, YU101 became carfilzomib/Kyprolis(r), which was approved by the FDA in 2012 for relapsed/refractory multiple myeloma. More recently, my lab has been focused on the flipside of protein turnover, i.e., developing a small molecule analogy to siRNA to induce protein knockdown. We have shown that this strategy, known as Proteolysis Targeting Chimerae (PROTACs) can effectively recruit targeted oncoproteins to E3 ubiquitin ligases for induced degradation, both in cell culture and in vivo. Having founded another biopharma, Arvinas, Inc., to focus on the application of this approach to nuclear hormone receptors in oncology, I propose here to develop this technology further to target truly undruggable proteins that are key oncogenic drivers. This innovative approach of `induced protein degradation' has the potential to be a new drug development paradigm that could have a significant impact by dramatically expanding the protein classes one can target pharmaceutically. Finally, for the past 19 years, I have focused on translating research from my lab into both new oncology-focused ventures and a FDA-approved drug, thus demonstrating truly `bench-to-bedside' research that is not common in academia today. This track record of innovation and execution within translational cancer research are strong predictors of continued future success.

 描述（由申请人提供）：制药行业陷入危机；不幸的是，后基因组时代并没有显着改变制药公司追求的蛋白质数量。新的抗癌药物靶点的缺乏导致了太多“效仿”药物的出现和浪费精力。为了满足这一需求，我的实验室致力于开发“受控蛋白质稳态”这一新领域。我们最初的努力集中在抑制蛋白质周转； 我们开发了一种新型蛋白酶体抑制剂 YU101，它是我实验室的新型肿瘤生物制药 Proteolix, Inc. 的基础。最终，YU101 成为 carfilzomib/Kyprolis(r)，于 2012 年获得 FDA 批准用于治疗复发/难治性多发性骨髓瘤。最近，我的实验室一直专注于蛋白质周转的另一面，即开发一种类似于 siRNA 的小分子来诱导蛋白质敲低。我们已经证明，这种被称为蛋白水解靶向嵌合体 (PROTAC) 的策略可以有效地将靶向癌蛋白招募到 E3 泛素连接酶中，以在细胞培养物和体内诱导降解。我成立了另一家生物制药公司 Arvinas, Inc.，专注于将这种方法应用于肿瘤学中的核激素受体，我在此建议进一步开发这项技术，以针对真正不可成药的蛋白质，这些蛋白质是关键的致癌驱动因素。这种“诱导蛋白质降解”的创新方法有可能成为一种新的药物开发范例，可以通过显着扩展药物靶向的蛋白质类别来产生重大影响。最后，在过去的 19 年里，我一直致力于将实验室的研究转化为以肿瘤学为重点的新企业和 FDA 批准的药物，从而展示了真正的“实验室到临床”研究，这在当今学术界并不常见。转化癌症研究中的创新和执行记录是未来持续成功的有力预测。