@misc{vohidov_andersen_economides_shipitsin_burenkova_ackley_vangamudi_gallagher_shieh_golder_et al._2020, title={Design of BET Inhibitor Prodrugs with Superior Efficacy and Devoid of Systemic Toxicities}, DOI={10.26434/chemrxiv.13241966.v1}, abstractNote={<div><p>Prodrugs engineered for preferential activation in diseased versus normal tissues offer immense potential to improve the therapeutic index of preclinical and clinical-stage active pharmaceutical ingredients that either cannot be developed otherwise or whose efficacy or tolerability it is highly desirable to improve. Such approaches, however, often suffer from trial-and-error design, precluding predictive design and optimization. Here, using BET bromodomain inhibitors (BETi)—a class of epigenetic regulators with proven anti-cancer activity but clinical development hindered by systemic adverse effects–– we introduce a platform that overcomes these challenges. Through tuning of traceless linkers appended to a "brush prodrug" scaffold, we demonstrate that it is possible to correlate <i>in vitro </i>prodrug activation kinetics with <i>in vivo </i>tumor pharmacokinetics, leading to novel BETi prodrugs with enhanced anti-tumor efficacy and devoid of dose-limiting toxicities. This work has immediate clinical implications, introducing principles for the predictive design of prodrugs and potentially overcoming hurdles in drug development. </p></div>}, publisher={American Chemical Society (ACS)}, author={Vohidov, Farrukh and Andersen, Jannik N. and Economides, Kyriakos D. and Shipitsin, Michail V. and Burenkova, Olga and Ackley, James C. and Vangamudi, Bhavatarini and Gallagher, Nolan M. and Shieh, Peyton and Golder, Matthew R. and et al.}, year={2020}, month={Nov} }