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Vohidov, Farrukh; Andersen, Jannik N; Economides, Kyriakos D; Shipitsin, Michail V; Burenkova, Olga; Ackley, James C; Vangamudi, Bhavatarini; Nguyen, Hung V.-T; Gallagher, Nolan M; Shieh, Peyton; Golder, Matthew R; Liu, Jenny; Dahlberg, William K; Ehrlich, Deborah J. C; Kim, Julie; Kristufek, Samantha L; Huh, Sung Jin; Neenan, Allison M; Baddour, Joelle; Paramasivan, Sattanathan; de Stanchina, Elisa; KC, Gaurab; Turnquist, David J; Saucier-Sawyer, Jennifer K; Kopesky, Paul W; Brady, Samantha W; Jessel, Michael J; Reiter, Lawrence A; Chickering, Donald E; Johnson, Jeremiah A; Blume-Jensen, Peter
Journal of the American Chemical Society, 03/2021, Letnik: 143, Številka: 12Journal Article
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.
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Dostop do baze podatkov JCR je dovoljen samo uporabnikom iz Slovenije. Vaš trenutni IP-naslov ni na seznamu dovoljenih za dostop, zato je potrebna avtentikacija z ustreznim računom AAI.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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