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 language | English |
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Pages (from-to) | 1459-1467 |
Number of pages | 9 |
Journal | ACS Medicinal Chemistry Letters |
Volume | 13 |
Issue number | 9 |
DOIs | |
State | Published - 8 Sep 2022 |
Bibliographical note
Publisher Copyright:© 2022 American Chemical Society. All rights reserved.
Keywords
- Alzheimer's disease
- CD47
- QC
- SIRPα
- cancer immunotherapy
- fibrosis
- fragment
- inhibitor
- isoQC
- metalloprotein