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.
J Am Chem Soc. 2021 Mar 31;143(12):4714-4724. doi: 10.1021/jacs.1c00312. Epub 2021 Mar 19.
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 prodrug activation kinetics with 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.
前药设计用于在疾病组织与正常组织中优先激活，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，这些成分要么无法开发，要么其疗效或耐受性需要极大改善。然而，这些方法往往受到反复试验的设计限制，无法进行预测性的合成和优化。在这里，我们使用溴结构域和末端结构域（BET）蛋白抑制剂（BETi）-一类具有明确抗癌潜力的表观遗传调节剂，但由于 TI 较窄，在很大程度上阻碍了其临床开发-引入了一种大分子前药平台，克服了这些挑战。通过调整连接到“瓶刷前药”支架上的无痕迹接头，我们证明了前药激活动力学与肿瘤药代动力学之间的相关性，从而能够在同种异体三阴性乳腺癌小鼠模型中，预测设计具有增强抗肿瘤功效且无剂量限制毒性的新型 BETi 前药。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了一个平台，并可能克服药物开发中的障碍。
