经典的低分子量药物旨在与具有受体或酶活性的生物靶点高亲和结合，并抑制它们的功能。然而，许多非受体或非酶性疾病蛋白似乎无法通过传统的药物方法治疗。这个限制被双功能分子PROTAC克服了，PROTAC能够与感兴趣的蛋白质和E3泛素连接酶复合物结合。这种相互作用导致POI的泛素化并随后在细胞质中进行蛋白质降解。在数百种作为底物受体的E3泛素连接酶复合物中，目前的PROTAC仅招募其中的几种，包括CRBN、cIAP1、VHL或MDM-2。本文将重点介绍招募CRBN E3泛素连接酶的PROTAC，并瞄准与肿瘤发生有关的多种蛋白质，例如转录因子、激酶、细胞因子、酶、抗凋亡蛋白和细胞受体。将讨论几种PROTAC的结构、化学和药代动力学特性、靶点亲和力以及体外和体内生物活性。还将强调可能影响PROTAC疗效并对未来PROTAC开发构成挑战的细胞机制。

The classical low-molecular-weight drugs are designed to bind with high affinity to the biological targets endowed with receptor or enzymatic activity, and inhibit their function. However, there are many non-receptor or non-enzymatic disease proteins that seem undruggable using the traditional drug approach. This limitation has been overcome by PROTACs, bifunctional molecules that are able to bind the protein of interest and the E3 ubiquitin ligase complex. This interaction results in the ubiquitination of POI and subsequent proteolysis in the cellular proteasome. Out of hundreds of proteins serving as substrate receptors in E3 ubiquitin ligase complexes, current PROTACs recruit only a few of them, including CRBN, cIAP1, VHL or MDM-2. This review will focus on PROTACs recruiting CRBN E3 ubiquitin ligase and targeting various proteins involved in tumorigenesis, such as transcription factors, kinases, cytokines, enzymes, anti-apoptotic proteins and cellular receptors. The structure of several PROTACs, their chemical and pharmacokinetic properties, target affinity and biological activity in vitro and in vivo, will be discussed. We will also highlight cellular mechanisms that may affect the efficacy of PROTACs and pose a challenge for the future development of PROTACs.