PROTACs to address the challenges facing small molecule inhibitors.

PROTACs to address the challenges facing small molecule inhibitors.
Eur J Med Chem. 2020 Nov 05;:112993
Authors: Martín-Acosta P, Xiao X
Abstract
Small molecule inhibitors of proteins represent important medicines and critical chemical tools to investigate the biology of the target proteins. Advances in various -omics technologies have fueled the pace of discovery of disease-relevant proteins. Translating these discoveries into human benefits requires us to develop specific chemicals to inhibit the proteins. However, traditional small molecule inhibitors binding to orthosteric or allosteric sites face significant challenges. These challenges include drug selectivity, therapy resistance as well as drugging undruggable proteins and multi-domain proteins. To address these challenges, PROteolysis TArgeting Chimera (PROTAC) has been proposed. PROTACs are heterobifunctional molecules containing a binding ligand for a protein of interest and E3 ligase-recruiting ligand that are connected through a chemical linker. Binding of a PROTAC to its target protein will bring a E3 ligase in close proximity to initiate polyubiquitination of the target protein ensuing its proteasome-mediated degradation. Unlike small molecule inhibitors, PROTACs achieve target protein degradation in its entirety in a catalytical fashion. In this review, we analyze recent advances in PROTAC design to discuss how PROTACs can address the challenges facing small molecule ...

Source: European Journal of Medicinal Chemistry - November 5, 2020 Category: Chemistry Authors: Martín-Acosta P, Xiao X Tags: Eur J Med Chem Source Type: research