Linkers as Game-changers in PROTAC Technology: Emphasizing General Trends in PROTAC Pharmacokinetics for their Rational Design
Carlotta Cecchini,
Sébastien Tardy,
Leonardo Scapozza
Affiliations
Carlotta Cecchini
Pharmaceutical Biochemistry/Chemistry, School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, CH-1206 Geneva; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland
Sébastien Tardy
Pharmaceutical Biochemistry/Chemistry, School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, CH-1206 Geneva; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland
Leonardo Scapozza
Pharmaceutical Biochemistry/Chemistry, School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, CH-1206 Geneva; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland
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.
