Protein degradation using proteolysis targeting chimeras (PROTACs) represents a promising therapeutic strategy. PROTACs are heterobifunctional molecules that consist of a target-binding moiety and an E3 ligase binding moiety, connected by a linker. These fragments are frequently united via amide bonds. While straightforward to synthesize, amides may impart suboptimal drug properties to the overall molecule. From a systems level perspective, we envisioned that the potency of PROTACs could be modulated through selection of reaction conditions─wherein different catalysts produce distinct linkers from the same two building blocks. We present a suite of BRD4 PROTAC degraders prepared via four new amine–acid coupling reactions alongside the classic amide coupling. Our findings reveal that variations in reaction conditions affect the physicochemical properties of PROTACs, resulting in a spectrum of properties. Notably, several new PROTACs demonstrated enhanced BRD4 degradation efficacy compared to those employing amide linkers, emphasizing the potential of systems chemistry as a therapeutic optimization strategy.

中文翻译：

---

用胺-酸偶联反应在系统水平上调节 BRD4 PROTACs 的效力


使用蛋白水解靶向嵌合体 （PROTAC） 进行蛋白质降解代表了一种很有前途的治疗策略。PROTAC 是异双功能分子，由一个靶标结合部分和一个 E3 连接酶结合部分组成，由接头连接。这些片段通常通过酰胺键结合。虽然合成简单，但酰胺可能会使整个分子的药物特性欠佳。从系统层面的角度来看，我们设想可以通过选择反应条件来调节 PROTAC 的效力，其中不同的催化剂从相同的两个构建单元产生不同的连接子。我们介绍了一套 BRD4 PROTAC 降解剂，通过四种新的胺-酸偶联反应和经典的酰胺偶联反应制备。我们的研究结果表明，反应条件的变化会影响 PROTACs 的物理化学性质，从而产生一系列性质。值得注意的是，与采用酰胺连接子的 PROTAC 相比，几种新的 PROTAC 表现出增强的 BRD4 降解功效，强调了系统化学作为治疗优化策略的潜力。