2-Amino-1,3,4-thiadiazoles as Glutaminyl Cyclases Inhibitors Increase Phagocytosis through Modification of CD47-SIRPα Checkpoint

Eunsun Park, Kyung Hee Song, Darong Kim, Minyoung Lee, Nguyen Van Manh, Hee Kim, Ki Bum Hong, Jeewoo Lee, Jie Young Song, Soosung Kang

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Glutaminyl cyclases (QC, isoQC) convert N-terminal glutamine or glutamate into pyroglutamate (pGlu) on substrates. IsoQC has recently been demonstrated to promote pGlu formation on the N-terminus of CD47, the SIRPα binding site, contributing to the "don't eat me" cancer immune signaling of CD47-SIRPα. We developed new QC inhibitors by applying a structure-based optimization approach starting from fragments identified through library screening. Screening of metal binding fragments identified 5-(1H-benzimidazol-5-yl)-1,3,4-thiadiazol-2-amine (9) as a potent fragment, and further modification provided 5-(1-(3-methoxy-4-(3-(piperidin-1-yl)propoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-1,3,4-thiadiazol-2-amine (22b) as a potent QC inhibitor. Treatment with 22b in A549 and H1975 lung cancer cells decreased the CD47/αhCD47-CC2C6 interaction, indicative of the CD47/SIRPα interaction, and enhanced the increased phagocytic activity of both THP-1 and U937 macrophages.

Original languageEnglish
Pages (from-to)1459-1467
Number of pages9
JournalACS Medicinal Chemistry Letters
Volume13
Issue number9
DOIs
StatePublished - 8 Sep 2022

Bibliographical note

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© 2022 American Chemical Society. All rights reserved.

Keywords

  • Alzheimer's disease
  • CD47
  • QC
  • SIRPα
  • cancer immunotherapy
  • fibrosis
  • fragment
  • inhibitor
  • isoQC
  • metalloprotein

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