Review of the impact of fragment-based drug design on PROTAC degrader discovery

Proteolysis targeting chimera (PROTAC) is an emerging therapeutic strategy using small molecules to induce ubiquitin-dependent degradation of proteins. Fragment-based drug design (FBDD) has achieved great success in the discovery of highly active PROTAC molecules. Here, we highlight the progress of FBDD in screening PROTAC molecules. Key features of the FBDD method and the procedure of designing PROTAC molecules by FBDD are summarized and analyzed. PROTAC molecules that is entered clinical studies has introduced as case studies to help understand the fragment-to-PROTAC optimization process. We also present the future trends of applying the FBDD method to screen PROTAC molecules. Thus, this review will provide helpful guidance for new PROTAC discoveries.