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Design of BET Inhibitor Prodrugs with Superior Efficacy and Devoid of Systemic Toxicities

submitted on 16.11.2020, 16:59 and posted on 17.11.2020, 11:13 by Farrukh Vohidov, Jannik N. Andersen, Kyriakos D. Economides, Michail V. Shipitsin, Olga Burenkova, James C. Ackley, Bhavatarini Vangamudi, Nolan M. Gallagher, Peyton Shieh, Matthew R. Golder, Jenny Liu, William K. Dahlberg, Hung V.-T. Nguyen, Deborah J. C. Ehrlich, Julie Kim, Sung Jin Huh, Allison M. Neenan, Joelle Baddour, Sattanathan Paramasivan, Elisa de Stanchina, Gaurab KC, David J. Turnquist, Jennifer K. Saucier-Sawyer, Paul W. Kopesky, Samantha W. Brady, Michael J. Jessel, Lawrence A. Reiter, Donald E. Chickering, Jeremiah Johnson, Peter Blume-Jensen

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 in vitro prodrug activation kinetics with in vivo 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.


NIH (1R01CA220468-01)


Email Address of Submitting Author




United States

ORCID For Submitting Author


Declaration of Conflict of Interest

F.V. and J.A.J. are named inventors on patent applications filed by the Massachusetts Institute of Technology on the linker compositions and bottlebrush polymer platform described in this work.