Biological and Medicinal Chemistry

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

Abstract

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.

Content

Thumbnail image of ChemRxiv_Manuscript.pdf
download asset ChemRxiv_Manuscript.pdf 2 MB [opens in a new tab]

Supplementary material

Thumbnail image of ChemRxiv_Supplementary Materials.pdf
download asset ChemRxiv_Supplementary Materials.pdf 2 MB [opens in a new tab]
ChemRxiv Supplementary Materials
Thumbnail image of ChemRxiv_Additional Materials and Methods.pdf
download asset ChemRxiv_Additional Materials and Methods.pdf 14 MB [opens in a new tab]
ChemRxiv Additional Materials and Methods