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

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2-Amino-1,3,4-thiadiazoles as Glutaminyl Cyclases Inhibitors Increase Phagocytosis through Modification of CD47-SIRPα Checkpoint
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2022-08-16 , DOI: 10.1021/acsmedchemlett.2c00256
Eunsun Park ₁ , Kyung-Hee Song ₂ , Darong Kim ₃ , Minyoung Lee ₄ , Nguyen Van Manh ₅ , Hee Kim ₄ , Ki Bum Hong ₃ , Jeewoo Lee ₅ , Jie-Young Song ₂ , Soosung Kang ₁

Affiliation

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.

中文翻译：

2-氨基-1,3,4-噻二唑作为谷氨酰胺环化酶抑制剂通过修饰 CD47-SIRPα 检查点增加吞噬作用

谷氨酰胺环化酶 (QC, isoQC) 将 N 末端谷氨酰胺或谷氨酸转化为底物上的焦谷氨酸 (pGlu)。IsoQC 最近已被证明可促进 CD47 N 末端（SIRPα 结合位点）上 pGlu 的形成，从而促成 CD47-SIRPα 的“不要吃我”癌症免疫信号传导。我们通过应用基于结构的优化方法开发了新的 QC 抑制剂，该方法从通过文库筛选识别的片段开始。筛选金属结合片段将 5-(1 H -benzimidazol-5-yl)-1,3,4-thiadiazol-2-amine ( 9 ) 鉴定为有效片段，进一步修饰提供 5-(1-(3-甲氧基-4-(3-(哌啶-1-基)丙氧基)苄基)-1 H-苯并[ d ]咪唑-5-基)-1,3,4-噻二唑-2-胺( 22b) 作为有效的 QC 抑制剂。在 A549 和 H1975 肺癌细胞中用22b处理降低了 CD47/αhCD47-CC2C6 相互作用，表明 CD47/SIRPα 相互作用，并增强了 THP-1 和 U937 巨噬细胞的吞噬活性增加。

更新日期：2022-08-16

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