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Design of BET Inhibitor Bottlebrush Prodrugs with Superior Efficacy and Devoid of Systemic Toxicities
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2021-03-19 , DOI: 10.1021/jacs.1c00312 Farrukh Vohidov 1 , Jannik N Andersen 2 , Kyriakos D Economides 2 , Michail V Shipitsin 2 , Olga Burenkova 2 , James C Ackley 2 , Bhavatarini Vangamudi 2 , Hung V-T Nguyen 1 , Nolan M Gallagher 1 , Peyton Shieh 1 , Matthew R Golder 1 , Jenny Liu 1, 2 , William K Dahlberg 2 , Deborah J C Ehrlich 1 , Julie Kim 1 , Samantha L Kristufek 1 , Sung Jin Huh 2 , Allison M Neenan 2 , Joelle Baddour 2 , Sattanathan Paramasivan 2 , Elisa de Stanchina 3 , Gaurab Kc 2 , David J Turnquist 2 , Jennifer K Saucier-Sawyer 2 , Paul W Kopesky 2 , Samantha W Brady 2 , Michael J Jessel 2 , Lawrence A Reiter 2 , Donald E Chickering 2 , Jeremiah A Johnson 1 , Peter Blume-Jensen 2
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2021-03-19 , DOI: 10.1021/jacs.1c00312 Farrukh Vohidov 1 , Jannik N Andersen 2 , Kyriakos D Economides 2 , Michail V Shipitsin 2 , Olga Burenkova 2 , James C Ackley 2 , Bhavatarini Vangamudi 2 , Hung V-T Nguyen 1 , Nolan M Gallagher 1 , Peyton Shieh 1 , Matthew R Golder 1 , Jenny Liu 1, 2 , William K Dahlberg 2 , Deborah J C Ehrlich 1 , Julie Kim 1 , Samantha L Kristufek 1 , Sung Jin Huh 2 , Allison M Neenan 2 , Joelle Baddour 2 , Sattanathan Paramasivan 2 , Elisa de Stanchina 3 , Gaurab Kc 2 , David J Turnquist 2 , Jennifer K Saucier-Sawyer 2 , Paul W Kopesky 2 , Samantha W Brady 2 , Michael J Jessel 2 , Lawrence A Reiter 2 , Donald E Chickering 2 , Jeremiah A Johnson 1 , Peter Blume-Jensen 2
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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.
中文翻译：
高效无全身毒性的BET抑制剂瓶刷前药的设计
专为在患病组织与正常组织中优先激活而设计的前药为改善临床前和临床阶段活性药物成分的治疗指数 (TI) 提供了巨大的潜力，这些药物成分无法以其他方式开发，或者其功效或耐受性非常需要提高。然而，此类方法通常会受到反复试验设计的影响，无法进行预测性综合和优化。在这里，使用溴结构域和末端 (BET) 蛋白抑制剂 (BETi)——一类具有被证明具有抗癌潜力但临床开发在很大程度上受窄 TI 阻碍的表观遗传调节剂——我们引入了一个克服这些挑战的大分子前药平台。通过调整附加到“瓶刷前药”支架的无痕连接器，我们证明了体外前药激活动力学与体内肿瘤药代动力学，使新型 BETi 前药的预测设计能够在同基因三阴性乳腺癌小鼠模型中具有增强的抗肿瘤功效且没有剂量限制性毒性。这项工作可能具有直接的临床意义，为预测性前药设计引入一个平台，并可能克服药物开发中的障碍。
更新日期：2021-03-31
中文翻译：
高效无全身毒性的BET抑制剂瓶刷前药的设计
专为在患病组织与正常组织中优先激活而设计的前药为改善临床前和临床阶段活性药物成分的治疗指数 (TI) 提供了巨大的潜力，这些药物成分无法以其他方式开发，或者其功效或耐受性非常需要提高。然而，此类方法通常会受到反复试验设计的影响，无法进行预测性综合和优化。在这里，使用溴结构域和末端 (BET) 蛋白抑制剂 (BETi)——一类具有被证明具有抗癌潜力但临床开发在很大程度上受窄 TI 阻碍的表观遗传调节剂——我们引入了一个克服这些挑战的大分子前药平台。通过调整附加到“瓶刷前药”支架的无痕连接器，我们证明了体外前药激活动力学与体内肿瘤药代动力学，使新型 BETi 前药的预测设计能够在同基因三阴性乳腺癌小鼠模型中具有增强的抗肿瘤功效且没有剂量限制性毒性。这项工作可能具有直接的临床意义，为预测性前药设计引入一个平台，并可能克服药物开发中的障碍。
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