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

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

Affiliations

  • 1 Cerevel Therapeutics, 222 Jacobs St., Cambridge, MA 02141, United States. Electronic address: shea.johnson@cerevel.com.
  • 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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