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.
|Salami, Jemilat; Alabi, Shanique; Willard, Ryan R et al. (2018) Androgen receptor degradation by the proteolysis-targeting chimera ARCC-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance. Commun Biol 1:100|
|Serebrenik, Yevgeniy V; Hellerschmied, Doris; Toure, Momar et al. (2018) Targeted protein unfolding uncovers a Golgi-specific transcriptional stress response. Mol Biol Cell 29:1284-1298|
|Bondeson, Daniel P; Smith, Blake E; Burslem, George M et al. (2018) Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead. Cell Chem Biol 25:78-87.e5|
|Burslem, George M; Ottis, Philipp; Jaime-Figueroa, Saul et al. (2018) Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure-Degradation Relationships. ChemMedChem 13:1508-1512|
|Burslem, George M; Smith, Blake E; Lai, Ashton C et al. (2018) The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study. Cell Chem Biol 25:67-77.e3|
|Salami, Jemilat; Crews, Craig M (2017) Waste disposal-An attractive strategy for cancer therapy. Science 355:1163-1167|
|Raina, Kanak; Crews, Craig M (2017) Targeted protein knockdown using small molecule degraders. Curr Opin Chem Biol 39:46-53|
|Saenz, D T; Fiskus, W; Qian, Y et al. (2017) Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells. Leukemia 31:1951-1961|
|Ottis, Philipp; Crews, Craig M (2017) Proteolysis-Targeting Chimeras: Induced Protein Degradation as a Therapeutic Strategy. ACS Chem Biol 12:892-898|
|Ottis, Philipp; Toure, Momar; Cromm, Philipp M et al. (2017) Assessing Different E3 Ligases for Small Molecule Induced Protein Ubiquitination and Degradation. ACS Chem Biol 12:2570-2578|
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