Investigating the cell permeability of proteolysis-targeting chimeras (PROTACs)
Investigating the cell permeability of proteolysis-targeting chimeras (PROTACs)
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研究蛋白水解靶向嵌合体 (PROTAC) 的细胞通透性
DOI：
10.1080/17460441.2023.2187047
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发表时间：
2023
影响因子：
6.3
通讯作者：
Demizu Yosuke
中科院分区：
文献类型：
--
作者：
Yokoo Hidetomo;Naito Mikihiko;Demizu Yosuke
蛋白水解靶向嵌合体（Proteolysis-targeting chimeras，PROTAC）是一种通过泛素-蛋白酶体系统降解靶蛋白的新型治疗方法。目前，十几种PROTAC正在进行临床试验。例如，ARV-110（bavdegalutamide）和ARV-471（ClinicalTrials. gov标识符：NCT 03888612、NCT 04072952）分别针对前列腺癌和乳腺癌中的雄激素受体和雌激素受体的药物组合物处于2期临床试验中。在结构上，PROTAC是由两个配体组成的嵌合分子-一个用于感兴趣的蛋白质（POI），一个用于泛素连接酶（E3）-通过接头连接。迄今为止，已经开发了几种PROTAC的E3配体，其包括Von Hippel-Lindau（VHL）、cereblon（CRBN）、凋亡蛋白抑制剂（IAP）和小鼠双微体2同源物（MDM 2）E3泛素连接酶的配体。PROTAC的构效关系研究通常集中在连接体结构上。例如，ARV-471和ARV-110含有具有哌啶和哌嗪部分的短而刚性的接头。具有环状可离子化基团的短亲脂性接头可增加细胞膜渗透性和溶解性，并赋予适度的代谢稳定性[1]。PROTAC的结构刚性化对于优化POI/PROTAC/E3连接酶三元复合物的几何形状可能是必要的，从而影响PROTAC功效。因此，化学修饰在帮助PROTAC满足吸收、分布、代谢和排泄（ADME）要求方面可能是重要的。与通常显示良好细胞渗透性的小分子降解剂如沙利度胺相反，大多数PROTAC显示差的细胞渗透性，至少部分是由于高分子量（通常超过800 Da）;这显著高于500 Da的“5法则”（Ro 5）标准，这是口服活性小分子药物的指南[2]。尽管略微降低分子量可能是可行的，但认为PROTAC的最小分子量约为650 Da。
Proteolysis-targeting chimeras (PROTACs) have emerged as a novel therapeutic modality for the degradation of target proteins via the ubiquitin-proteasome system. Currently, more than a dozen PROTACs are under clinical trials. For example, ARV-110 (bavdegalutamide) and ARV-471 (ClinicalTrials. gov Identifiers: NCT03888612, NCT04072952) against androgen receptor and estrogen receptor in prostate and breast cancers, respectively, are in Phase 2 clinical trials. Structurally, PROTACs are chimeric molecules composed of two ligands–one for the protein of interest (POI) and one for a ubiquitin ligase (E3)–connected via a linker. Several E3 ligands for PROTACs have been developed so far, which include the ligands for the Von Hippel–Lindau (VHL), cereblon (CRBN), inhibitor of apoptosis proteins (IAPs), and mouse double minute 2 homolog (MDM2) E3 ubiquitin ligases. Structure–activity relationship studies of PROTACs often focus on the linker structures. For example, ARV-471 and ARV-110 contain short and rigid linkers with piperidine and piperazine moieties. Short lipophilic linkers with cyclic ionizable groups can increase cell-membrane permeability and solubility, and impart moderate metabolic stability [1]. Structural rigidification of PROTACs may be necessary to optimize the geometry of the POI/PROTAC/E3 ligase ternary complex, thereby affecting PROTAC efficacy. Thus, chemical modifications are likely to be important in helping PROTACs meet absorption, distribution, metabolism, and excretion (ADME) requirements.In contrast to small-molecule degraders such as thalidomide that generally show good cell permeability, most PROTACs show poor cell permeability due at least in part to a high molecular weight (usually over 800 Da); this is significantly higher than the ‘rule-of-5’(Ro5) criteria of 500 Da, which is a guideline for orally active small-molecule drugs [2]. Even though a slight reduction in molecular weight may be feasible, the smallest molecular weight of PROTACs is considered to be approximately 650 Da. Other molecular properties that are listed in Ro5 and Veber’s rules must also be considered in