Discovery and Hit to Lead Optimization of Macrocyclic Peptides as Novel Tropomyosin Receptor Kinase A Antagonists

  • J Med Chem. 2024 Jul 11;67(13):11197-11208. doi: 10.1021/acs.jmedchem.4c00715.
Toru Yamada  1 ,  Kousuke Mihara  2 ,  Taichi Ueda  2 ,  Daisuke Yamauchi  2 ,  Masaya Shimizu  2 ,  Azusa Ando  2 ,  Kei Mayumi  3 ,  Zenzaburo Nakata  2 ,  Hidenori Mikamiyama  2
Affiliations
  • 1. Biopharmaceutical Research Division, Shionogi Pharmaceutical Research Center, Toyonaka , Osaka 561-0825, Japan.
  • 2. Pharmaceutical Research Division, Shionogi Pharmaceutical Research Center, Toyonaka , Osaka 561-0825, Japan.
  • 3. Pharmaceutical Development Division, Yodoyabashi Office, Osaka , Osaka 541-0042, Japan.
PMID: 38950284 DOI: 10.1021/acs.jmedchem.4c00715
Abstract

Tropomyosin receptor kinases (Trks) are Receptor Tyrosine Kinases activated by Neurotrophic Factors, called neurotrophins. Among them, TrkA interacts with the nerve growth factor (NGF), which leads to pain induction. mRNA-display screening was carried out to discover a hit compound 2, which inhibits protein-protein interactions between TrkA and NGF. Subsequent structure optimization improving phosphorylation inhibitory activity and serum stability was pursued using a unique process that took advantage of the peptide being synthesized by translation from mRNA. This gave peptide 19, which showed an analgesic effect in a rat incisional pain model. The peptides described here can serve as a new class of analgesics, and the structure optimization methods reported provide a strategy for discovering new peptide drugs.

Products