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2-Amino-1,3,4-thiadiazoles as Glutaminyl Cyclases Inhibitors Increase Phagocytosis through Modification of CD47-SIRP alpha Checkpoint
- Title
- 2-Amino-1,3,4-thiadiazoles as Glutaminyl Cyclases Inhibitors Increase Phagocytosis through Modification of CD47-SIRP alpha Checkpoint
- Authors
- Park, Eunsun; Song, Kyung-Hee; Kim, Darong; Lee, Minyoung; Nguyen Van Manh; Kim, Hee; Hong, Ki Bum; Lee, Jeewoo; Song, Jie-Young; Kang, Soosung
- Ewha Authors
- 강수성
- SCOPUS Author ID
- 강수성
- Issue Date
- 2022
- Journal Title
- ACS MEDICINAL CHEMISTRY LETTERS
- ISSN
- 1948-5875
- Citation
- ACS MEDICINAL CHEMISTRY LETTERS vol. 13, no. 9, pp. 1459 - 1467
- Keywords
- QC; isoQC; inhibitor; metalloprotein; fragment; CD47; SIRP?; cancer immunotherapy; fibrosis; Alzheimer?s disease
- Publisher
- AMER CHEMICAL SOC
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- 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 SIRP alpha binding site, contributing to the & ldquo;don & rsquo;t eat me & rdquo; cancer immune signaling of CD47-SIRP alpha. 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/alpha hCD47-CC2C6 interaction, indicative of the CD47/SIRP alpha interaction, and enhanced the increased phagocytic activity of both THP-1 and U937 macrophages. <comment>Superscript/Subscript Available</comment
- DOI
- 10.1021/acsmedchemlett.2c00256
- Appears in Collections:
- 약학대학 > 약학과 > Journal papers
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