William J Netzer, Anjana Sinha, Mondana Ghias, Emily Chang, Katherina Gindinova, Emily Mui, Ji-Seon Seo, Subhash Sinha
{"title":"拉伸异构伊马替尼类似物的结构包络,通过调节APP的β和γ分泌酶裂解减少β淀粉样蛋白的产生","authors":"William J Netzer, Anjana Sinha, Mondana Ghias, Emily Chang, Katherina Gindinova, Emily Mui, Ji-Seon Seo, Subhash Sinha","doi":"10.1101/2024.07.14.602669","DOIUrl":null,"url":null,"abstract":"We previously showed that the anticancer drug imatinib mesylate (IMT, trade name: Gleevec) and a chemically distinct compound, DV2-103 (a kinase-inactive derivative of the potent Abl and Src kinase inhibitor, PD173955) lower Aβ levels at low micromolar concentrations primarily through a lysosome-dependent mechanism that renders APP less susceptible to proteolysis by BACE1 without directly inhibiting BACE1 enzymatic activity, or broadly inhibiting the processing of other BACE1 substrates. Additionally, IMT indirectly inhibits γ-secretase and stimulates autophagy, and thus may decrease Aβ levels through multiple pathways. In two recent studies we demonstrated similar effects on APP metabolism caused by derivatives of IMT and DV2-103. In the present study we investigated how so many structurally diverse compounds affect APP metabolism in the same way, with similar potencies and production of APP metabolites. To this end, we synthesized and tested radically altered IMT regioisomers that possess medium structural similarity to IMT. Independent of structural similarity, these isomers manifest widely differing potencies in altering APP metabolism. These will enable us to choose the most potent isomers for further derivatization.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"39 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Stretching the structural envelope of isomeric imatinib analogs that reduce β-amyloid production by modulating both β- and γ-secretase cleavages of APP\",\"authors\":\"William J Netzer, Anjana Sinha, Mondana Ghias, Emily Chang, Katherina Gindinova, Emily Mui, Ji-Seon Seo, Subhash Sinha\",\"doi\":\"10.1101/2024.07.14.602669\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"We previously showed that the anticancer drug imatinib mesylate (IMT, trade name: Gleevec) and a chemically distinct compound, DV2-103 (a kinase-inactive derivative of the potent Abl and Src kinase inhibitor, PD173955) lower Aβ levels at low micromolar concentrations primarily through a lysosome-dependent mechanism that renders APP less susceptible to proteolysis by BACE1 without directly inhibiting BACE1 enzymatic activity, or broadly inhibiting the processing of other BACE1 substrates. Additionally, IMT indirectly inhibits γ-secretase and stimulates autophagy, and thus may decrease Aβ levels through multiple pathways. In two recent studies we demonstrated similar effects on APP metabolism caused by derivatives of IMT and DV2-103. In the present study we investigated how so many structurally diverse compounds affect APP metabolism in the same way, with similar potencies and production of APP metabolites. To this end, we synthesized and tested radically altered IMT regioisomers that possess medium structural similarity to IMT. Independent of structural similarity, these isomers manifest widely differing potencies in altering APP metabolism. These will enable us to choose the most potent isomers for further derivatization.\",\"PeriodicalId\":501518,\"journal\":{\"name\":\"bioRxiv - Pharmacology and Toxicology\",\"volume\":\"39 1\",\"pages\":\"\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-07-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"bioRxiv - Pharmacology and Toxicology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1101/2024.07.14.602669\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"bioRxiv - Pharmacology and Toxicology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2024.07.14.602669","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Stretching the structural envelope of isomeric imatinib analogs that reduce β-amyloid production by modulating both β- and γ-secretase cleavages of APP
We previously showed that the anticancer drug imatinib mesylate (IMT, trade name: Gleevec) and a chemically distinct compound, DV2-103 (a kinase-inactive derivative of the potent Abl and Src kinase inhibitor, PD173955) lower Aβ levels at low micromolar concentrations primarily through a lysosome-dependent mechanism that renders APP less susceptible to proteolysis by BACE1 without directly inhibiting BACE1 enzymatic activity, or broadly inhibiting the processing of other BACE1 substrates. Additionally, IMT indirectly inhibits γ-secretase and stimulates autophagy, and thus may decrease Aβ levels through multiple pathways. In two recent studies we demonstrated similar effects on APP metabolism caused by derivatives of IMT and DV2-103. In the present study we investigated how so many structurally diverse compounds affect APP metabolism in the same way, with similar potencies and production of APP metabolites. To this end, we synthesized and tested radically altered IMT regioisomers that possess medium structural similarity to IMT. Independent of structural similarity, these isomers manifest widely differing potencies in altering APP metabolism. These will enable us to choose the most potent isomers for further derivatization.