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

• DOI: 10.1021/jacs.1c00312
• Publication Date: 2021-03-19T18:14:20Z
• Authors: Farrukh Vohidov; Jannik N. Andersen; Kyriakos D. Econo...; Michail V. Shipitsin; Olga Burenkova; James C. Ackley; Bhavatarini Vanga...; Hung V.-T. Nguyen; Nolan M. Gallagher; Peyton Shieh; Matthew R. Golder; Jenny Liu; William K. Dahlberg; Deborah J. C. Ehr...; Julie Kim; Samantha L. Krist...; Sung Jin Huh; Allison M. Neenan; Joelle Baddour; Sattanathan Param...; Elisa de Stanchina; Gaurab KC; David J. Turnquist; Jennifer K. Sauci...; Paul W. Kopesky; Samantha W. Brady; Michael J. Jessel; Lawrence A. Reiter; Donald E. Chickering; Jeremiah A. Johnson; Peter Blume-Jensen
• Keywords: 0301 basic medicine; prodrug platform; Chemical Sciences not elsewhere classified; vivo tumor pharmacokinetics; novel BETi prodrugs; Macromolecular Substances; Immunology; Information Systems not elsewhere classified; antitumor efficacies; Antineoplastic Agents; trial-and-error design; Biochemistry; syngeneic triple-negative breast ca.; Mice; 03 medical and health sciences; traceless linkers; BET Inhibitor Bottlebrush Prodrugs; Systemic Toxicities Prodrugs; Animals; Humans; Prodrugs; Such approaches; Cancer; protein inhibitors; Cell Proliferation; Pharmacology; Superior Efficacy; Molecular Structure; tissues offer; Mammary Neoplasms, Experimental; Proteins; prodrug activation kinetics; drug development; prodrug design; 3. Good health; Drug Design; Medicine; TI; Drug Screening Assays, Antitumor; dose-limiting toxicities; Biotechnology; Biological Sciences not elsewhere classified

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.