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.
The function of many rogue, disease-causing proteins cannot not be easily blocked using a small molecule drug approach, hence they are `undruggable'. To address this, we propose to simply eliminate these unwanted proteins from the body instead of trying to use drugs to block their function. Here we describe the development of a new class of drugs that target `undruggable' proteins for destruction and propose to implement this new pharmaceutical strategy against five `undruggable' transcription factors that play key roles in oncology.
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