Linkers as Game-changers in PROTAC Technology: Emphasizing General Trends in PROTAC Pharmacokinetics for their Rational Design

被引：10

作者：

Cecchini, Carlotta ^{[1
,2
]}

Tardy, Sebastien ^{[1
,2
]}

Scapozza, Leonardo ^{[1
,2
]}

机构：

[1] Univ Geneva, Sch Pharmaceut Sci, Pharmaceut Biochem Chem, Rue Michel Servet 1, CH-1206 Geneva, Switzerland

[2] Univ Geneva, Inst Pharmaceut Sci Western Switzerland, Geneva, Switzerland

来源：

CHIMIA | 2022年 / 76卷 / 04期

基金：

瑞士国家科学基金会;

关键词：

Drug metabolism and pharmacokinetics; Linker optimization; Proteolysis Targeting Chimeras (PROTACs); Targeted protein degradation; SPACE;

D O I：

10.2533/chimia.2022.341

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Proteolysis Targeting Chimeras (PROTACs) are heterobifunctional molecules that act as degraders. They selectively remove disease-associated proteins by hijacking the Ubiquitin-Proteasome System (UPS). Chemically, they consist of three parts: an E3 ligase ligand, a target of interest (TOI) ligand, and a linker, which connects the two moieties. The rapid expansion of PROTAC technology as an innovative therapeutic modality in cancer fostered the drug discovery effort to optimize their physicochemical properties. Due to their large size, their features are far from the traditional 'drug-like' properties. This short review highlights some of the main structural features in the linker component to optimize the PROTAC Drug Metabolism and Pharmacokinetics (DMPK) profile. In particular, we discuss aspects related to solubility, cell permeability, active transporters efflux, and metabolic stability.

引用

页码：341 / 345

页数：5

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