Development and structure-activity relationship of tacrine derivatives as highly potent CDK2/9 inhibitors for the treatment of cancer
CDK2/9 are members of the CDKs family, which play key roles in the occurrence and development of many cancers by regulating cell cycle and transcriptional prolongation, respectively. To further optimize and discuss the structure-activity relationships (SARs), a series of tacrine-based compounds were...
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Published in | European journal of medicinal chemistry Vol. 242; p. 114701 |
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Main Authors | , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Elsevier Masson SAS
15.11.2022
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Subjects | |
Online Access | Get full text |
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Summary: | CDK2/9 are members of the CDKs family, which play key roles in the occurrence and development of many cancers by regulating cell cycle and transcriptional prolongation, respectively. To further optimize and discuss the structure-activity relationships (SARs), a series of tacrine-based compounds were designed and synthesized from the compound ZLWT-37, which was studied by our group previously but no detailed SARs study was conducted on CDK2/9. Among this series, compounds ZLMT-12 (35) exhibited the most potent antiproliferative activity (GI50 = 0.006 μM for HCT116) and superior CDK2/9 inhibitory properties (CDK2: IC50 = 0.011 μM, CDK9: IC50 = 0.002 μM). Meanwhile, ZLMT-12 showed a weak inhibitory effect on acetylcholinesterase (AChE, IC50 = 19.023 μM) and butyrylcholinesterase (BuChE, IC50 = 2.768 μM). In addition, ZLMT-12 can suppress colony formation and migration in HCT116 cells, as well as induce the apoptosis and arrest the cell cycle in the S phase and G2/M phase. In vivo investigations revealed that ZLMT-12 inhibits tumor growth in the HCT116 xenograft tumor model at a low dose of 10 mg/kg without causing hepatotoxicity. The acute toxicity test showed low toxicity with a median lethal dosage (LD50) of 104.417 mg/kg. These findings showed that ZLMT-12 might be used as a drug candidate by targeting CDK2/9.
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•Synthesis of novel tacrine derivatives as CDK2/9 inhibitors for cancer therapeutics.•ZLMT-12 showed superior antiproliferative activity and CDK2/9 inhibitory activity.•The detailed SARs of antiproliferative activity and CDK2/9 inhibitory potency were discussed.•ZLMT-12 exhibits promising antitumor activity. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0223-5234 1768-3254 |
DOI: | 10.1016/j.ejmech.2022.114701 |