Open AccessDesign of BET Inhibitor Bottlebrush Prodrugs with Superior Efficacy and Devoid of Systemic Toxicities
Author(s) -
Farrukh Vohidov,
Jannik N. Andersen,
Kyriakos D. Economides,
Michail Shipitsin,
Olga Burenkova,
James C. Ackley,
Bhavatarini Vangamudi,
Hung V.-T. Nguyen,
Nolan M. Gallagher,
Peyton Shieh,
Matthew R. Golder,
Jenny Liu,
William K. Dahlberg,
D. J. Ehrlich,
Julie Kim,
Samantha L. Kristufek,
Sung Jin Huh,
Allison M. Neenan,
Joelle Baddour,
Sattanathan Paramasivan,
Elisa de Stanchina,
Gaurab Kc,
David Turnquist,
Jennifer K. Saucier-Sawyer,
Paul W. Kopesky,
Samantha Brady,
Michael J. Jessel,
Lawrence A. Reiter,
Donald E. Chickering,
Jeremiah A. Johnson,
Peter BlumeJensen
Publication year - 2021
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.1c00312
Subject(s) - prodrug , chemistry , adept , in vivo , pharmacology , drug , pharmacokinetics , in vitro , limiting , tolerability , computational biology , biochemistry , medicine , biology , mechanical engineering , microbiology and biotechnology , engineering , adverse effect
Prodrugs engineered for preferential activation in diseased versus normal tissues offer immense potential to improve the therapeutic indexes (TIs) 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 synthesis and optimization. Here, using bromodomain and extra-terminal (BET) protein inhibitors (BETi)-a class of epigenetic regulators with proven anticancer potential but clinical development hindered in large part by narrow TIs-we introduce a macromolecular prodrug platform that overcomes these challenges. Through tuning of traceless linkers appended to a "bottlebrush prodrug" scaffold, we demonstrate correlation of in vitro prodrug activation kinetics with in vivo tumor pharmacokinetics, enabling the predictive design of novel BETi prodrugs with enhanced antitumor efficacies and devoid of dose-limiting toxicities in a syngeneic triple-negative breast cancer murine model. This work may have immediate clinical implications, introducing a platform for predictive prodrug design and potentially overcoming hurdles in drug development.