[Development of Protein Knockdown Technology as Emerging Drug Discovery Strategy].

[Development of Protein Knockdown Technology as Emerging Drug Discovery Strategy]. Yakugaku Zasshi. 2018;138(9):1135-1143 Authors: Ohoka N Abstract 　Protein knockdown technologies based on small molecules are attracting considerable attention in the pharmaceutical industry as a strategy for novel drug discovery. We and others have developed such compounds, designated as Specific and Nongenetic Inhibitor of Apoptosis Protein (IAP)-dependent Protein Erasers (SNIPERs), proteolysis-targeting chimeras (PROTACs), and Degronimids, which induce selective degradation of target proteins. These compounds contain two different ligands, specific for an ubiquitin E3 ligase and for a target protein, respectively, connected by a linker. SNIPERs, PROTACs, and Degronimids are designed to cross-link E3 ligase and the target protein to induce polyubiquitylation and proteasomal degradation of the target protein within cells. To recruit the von Hippel-Lindau (VHL) E3 ligase complex and the cereblon (CRBN) E3 ligase complex, a VHL inhibitor and a thalidomide derivative have been integrated into PROTAC and Degronimid constructs, respectively. Similarly, an IAP antagonist has been incorporated into SNIPERs to recruit cellular inhibitor of apoptosis protein 1 (cIAP1) or X-linked inhibitor of apoptosis protein (XIAP) E3 ligase. To date, a range of such compounds have been developed, allowing selective degradation of a variety of proteins, including estrogen ...
Source: Yakugaku Zasshi : Journal of the Pharmaceutical Society of Japan - Category: Drugs & Pharmacology Authors: Tags: Yakugaku Zasshi Source Type: research