Discovery of the first selective, small-molecule GFRα2/3 inhibitors through DNA-encoded library technology

  • Bioorg Med Chem Lett. 2024 Sep 15:110:129889. doi: 10.1016/j.bmcl.2024.129889.
Shea L Johnson  1 ,  Galen Missig  2 ,  Minghua Wang  2 ,  Kosalvisal Ouk  2 ,  Kushali Gupta  2 ,  Hanh Nho Nguyen  2 ,  May Fern Toh  2 ,  Tammy Szu-Yu Ho  2 ,  David Gray  2 ,  Hongjun Zhang  2 ,  Yong Mi Choi-Sledeski  2 ,  Claude Barberis  2 ,  David J Stone  2 ,  Sokhom Pin  2 ,  Jongwon Lim  2
Affiliations
  • 1. Cerevel Therapeutics, 222 Jacobs St., Cambridge, MA 02141, United States. Electronic address: [email protected].
  • 2. Cerevel Therapeutics, 222 Jacobs St., Cambridge, MA 02141, United States.
PMID: 39004318 DOI: 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.

Keywords
DEL; DNA-encoded libraries; GFRα; Itch; Pain.
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