Shea L. Johnson; Galen Missig; Minghua Wang; Kosalvisal Ouk; Kushali Gupta; Hanh Nho Nguyen; May Fern Toh; Tammy Szu-Yu Ho; David Gray; Hongjun Zhang; Yong Mi Choi-Sledeski; Claude Barberis; David J. Stone; Sokhom Pin; Jongwon Lim
Bioorg. Med. Chem. Lett., 2024, 110, 129889
https://doi.org/10.1016/j.bmcl.2024.129889

Abstract

Studies have shown that disrupting the formation of the ligand-RET-GFRα complex could be an effective way of treating pain and itch. Compared to traditional high-throughput screens, DNA encoded libraries (DELs) have distinguished themselves as a powerful technology for hit identification in recent years. The present work demonstrates the use of DEL technology identifying compound 16 as the first GFRa2/GFRa3 small molecule inhibitor (0.1/0.2 μM respectively) selective over RET. This molecule represents an opportunity to advance the development of small-molecule inhibitors targeting the GFRα-RET interface for the treatment of pain and itch.