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

Autor: Vohidov F; Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Andersen JN; XTuit Pharmaceuticals, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Economides KD; XTuit Pharmaceuticals, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Shipitsin MV; XTuit Pharmaceuticals, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Burenkova O; XTuit Pharmaceuticals, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Ackley JC; XTuit Pharmaceuticals, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Vangamudi B; XTuit Pharmaceuticals, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Nguyen HV; Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Gallagher NM; Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Shieh P; Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Golder MR; Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Liu J; Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.; XTuit Pharmaceuticals, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Dahlberg WK; XTuit Pharmaceuticals, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Ehrlich DJC; Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Kim J; Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Kristufek SL; Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Huh SJ; XTuit Pharmaceuticals, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Neenan AM; XTuit Pharmaceuticals, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Baddour J; XTuit Pharmaceuticals, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Paramasivan S; XTuit Pharmaceuticals, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., de Stanchina E; Memorial Sloan Kettering Cancer Center, 417 E 68th St, New York, New York 10065, United States., Kc G; XTuit Pharmaceuticals, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Turnquist DJ; XTuit Pharmaceuticals, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Saucier-Sawyer JK; XTuit Pharmaceuticals, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Kopesky PW; XTuit Pharmaceuticals, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Brady SW; XTuit Pharmaceuticals, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Jessel MJ; XTuit Pharmaceuticals, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Reiter LA; XTuit Pharmaceuticals, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Chickering DE; XTuit Pharmaceuticals, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States., Johnson JA; Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Blume-Jensen P; XTuit Pharmaceuticals, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
Jazyk: angličtina
Zdroj: Journal of the American Chemical Society [J Am Chem Soc] 2021 Mar 31; Vol. 143 (12), pp. 4714-4724. Date of Electronic Publication: 2021 Mar 19.
DOI: 10.1021/jacs.1c00312
Abstrakt: 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.
Databáze: MEDLINE
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