Inducing Protein Degradation: A New Pharmaceutical Paradigm

 描述(由申请人提供)：制药行业正处于危机之中；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。由于缺乏新的抗癌药物靶点，导致了太多的“我也”药物和浪费的努力。为了满足这一需求，我的实验室专注于开发“受控蛋白质稳定”这一新领域。我们最初的努力集中在抑制蛋白质周转； 我们开发了一种新的蛋白酶体抑制剂YU101，它是我实验室基于肿瘤学的新生物制药Proteolix，Inc.的基础。最终，YU101成为carfilzomib/Kyprolis(R)，它于2012年被FDA批准用于复发/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，即开发一种与siRNA类似的小分子来诱导蛋白质击倒。我们已经证明，这种被称为嵌合体蛋白水解靶向(PROTACs)的策略可以有效地将靶向癌蛋白招募到E3泛素连接酶以诱导降解，无论是在细胞培养中还是在体内。在建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后，我建议在这里进一步开发这项技术，以瞄准真正不可药物的蛋白质，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，通过极大地扩大可作为药物靶标的蛋白质类别而产生重大影响。最后，在过去的19年里，我一直专注于将我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，从而真正展示了当今学术界不常见的“床到床”研究。这种在转化型癌症研究中的创新和执行的记录是未来继续成功的强有力的预测。

 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.