Open AccessLinkers as Game-changers in PROTAC Technology: Emphasizing General Trends in PROTAC Pharmacokinetics for their Rational Design
Author(s) -
Carlotta Cecchini,
Sébastien Tardy,
Léonardo Scapozza
Publication year - 2022
Publication title -
chimia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.387
H-Index - 55
eISSN - 2673-2424
pISSN - 0009-4293
DOI - 10.2533/chimia.2022.341
Subject(s) - linker , ubiquitin ligase , proteasome , drug discovery , proteolysis , chemistry , pharmacokinetics , efflux , dna ligase , cell permeability , computational biology , combinatorial chemistry , pharmacology , ubiquitin , biochemistry , biology , computer science , enzyme , gene , operating system
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 structural modifications in the linker component to optimize the PROTAC Drug Metabolism and Pharmacokinetics (DMPK) profile. In particular, we discussed aspects related to solubility, cell permeability, active transporters efflux and, metabolic stability.