Development of BromoTag: A “Bump-and-Hole”–PROTAC System to Induce Potent, Rapid, and Selective Degradation of Tagged Target Proteins,Journal of Medicinal Chemistry

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Development of BromoTag: A “Bump-and-Hole”–PROTAC System to Induce Potent, Rapid, and Selective Degradation of Tagged Target Proteins
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-10-15 , DOI: 10.1021/acs.jmedchem.1c01532
Adam G Bond ₁ , Conner Craigon ₁ , Kwok-Ho Chan ₁ , Andrea Testa ₁ , Athanasios Karapetsas ₂ , Rotimi Fasimoye ₂ , Thomas Macartney ₂ , J Julian Blow ₃ , Dario R Alessi ₂ , Alessio Ciulli ₁

Affiliation

Small-molecule-induced protein depletion technologies, also called inducible degrons, allow degradation of genetically engineered target proteins within cells and animals. Here, we design and develop the BromoTag, a new inducible degron system comprising a Brd4 bromodomain L387A variant as a degron tag that allows direct recruitment by heterobifunctional bumped proteolysis targeting chimeras (PROTACs) to hijack the VHL E3 ligase. We describe extensive optimization and structure–activity relationships of our bump-and-hole–PROTACs using a CRISPR knock-in cell line expressing model target BromoTag-Brd2 at endogenous levels. Collectively, our cellular and mechanistic data qualifies bumped PROTAC AGB1 as a potent, fast, and selective degrader of BromoTagged proteins, with a favorable pharmacokinetic profile in mice. The BromoTag adds to the arsenal of chemical genetic degradation tools allowing us to manipulate protein levels to interrogate the biological function and therapeutic potential in cells and in vivo.

中文翻译：

BromoTag 的开发：“Bump-and-Hole”-PROTAC 系统可诱导标记靶蛋白的有效、快速和选择性降解

小分子诱导的蛋白质消耗技术，也称为诱导降解决定子，可以降解细胞和动物内的基因工程目标蛋白质。在这里，我们设计和开发了 BromoTag，一种新的诱导型降解决定子系统，包含 Brd4 溴结构域 L387A 变体作为降解决定子标签，允许通过异双功能碰撞蛋白水解靶向嵌合体 (PROTAC) 直接招募来劫持 VHL E3 连接酶。我们使用在内源水平表达模型目标 BromoTag-Brd2 的 CRISPR 敲入细胞系描述了我们的凹凸-孔 PROTAC 的广泛优化和结构-活性关系。总的来说，我们的细胞和机制数据证明，碰撞的 PROTAC AGB1 是一种有效、快速、选择性的 BromoTagged 蛋白降解剂，在小鼠中具有良好的药代动力学特征。 BromoTag 增加了化学遗传降解工具库，使我们能够操纵蛋白质水平来探究细胞和体内的生物功能和治疗潜力。

更新日期：2021-10-28

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