Proteolysis Targeting Chimera (PROTAC): A Paradigm-Shifting Approach in Small Molecule Drug Discovery.

Proteolysis Targeting Chimera (PROTAC): A Paradigm-Shifting Approach in Small Molecule Drug Discovery.
Curr Top Med Chem. 2018 Oct 09;:
Authors: Wang P, Zhou J
Abstract
Great success has been achieved in small molecule drug discovery programs, making extraordinary contributions for human health, especially in targeted therapy. Taking anticancer drug discovery as an example, small molecules traditionally inhibit the target protein enzyme activities and induce cancer cell apoptosis through the target binding. However, the target protein within tumor cells often recovers its activities, leading to acquired drug-resistance through the overexpression of the target protein or the generation of new mutations in the target protein [1]. Intriguingly, researchers are now employing a novel approach using small molecules to knock down the functional target protein instead of inhibiting the target protein activity. This approach utilizes, in part, a mammalian cellular system known as the ubiquitin-proteasome system (UPS) that decomposes unnecessary or unfit proteins. Specially designed small molecules can hijack the UPS by tagging the target protein as a protein for degradation and subsequently promoting a signal for degradation by the proteasome, which may eventually inhibit tumor cell proliferation [2]. Based upon this mechanism, the utilization of proteolysis targeting chimera (PROTAC) has emerged as a paradigm-shifting approach and opened new...

Source: Current Topics in Medicinal Chemistry - October 9, 2018 Category: Chemistry Authors: Wang P, Zhou J Tags: Curr Top Med Chem Source Type: research