Abstract
The DNA methyltransferases (DNMTs) were found in mammals to maintain DNA methylation. Among them, DNMT1 was the first identified, and it is an attractive target for tumour chemotherapy. DC_05 and DC_517 have been reported in our previous work, which is non-nucleoside DNMT1 inhibitor with low micromolar IC50 values and significant selectivity towards other S-adenosyl-L-methionine (SAM)-dependent protein methyltransferases. In this study, through a process of similarity-based analog searching, a series of DNMT1 inhibitors were designed, synthesized, and evaluated as anticancer agents. SAR studies were conducted based on enzymatic assays. And most of the compounds showed strong inhibitory activity on human DNMT1, especially WK-23 displayed a good inhibitory effect on human DNMT1 with an IC50 value of 5.0 µM. Importantly, the pharmacokinetic (PK) profile of WK-23 was obtained with quite satisfying oral bioavailability and elimination half-life. Taken together, WK-23 is worth developing as DNMT1-selective therapy for the treatment of malignant tumour.
Keywords:
A549 cell lines; DNMT1 inhibitor; HCT116 cell lines; antitumor activity; pharmacokinetic.
MeSH terms
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Animals
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Antineoplastic Agents* / pharmacology
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Carbazoles / pharmacology
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Cell Line, Tumor
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Cell Proliferation
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DNA (Cytosine-5-)-Methyltransferases / metabolism
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DNA Methylation
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DNA Modification Methylases / metabolism
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Humans
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Mammals / metabolism
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Neoplasms*
Substances
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Antineoplastic Agents
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Carbazoles
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DNA Modification Methylases
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DNA (Cytosine-5-)-Methyltransferases
Grants and funding
This work was supported by the Key-Area Research and Development Program of Guangdong Province (No. 2020B1111110007); the National Natural Science Foundation of China (Nos. 81202398, 81703415, and 21820102008); The special foundation of Guangzhou Key Laboratory (No. 202002010004); Natural Science Foundation of Guangdong Province (Nos. 2017B030314166 and 2022A1515010103); Special Funds for Inheriting and Developing the Traditional Chinese Medicine from TCM Bureau of Guangdong Province (No. 20191142); the Specific Research Fund for TCM Science and Technology of Guangdong Provincial Hospital of Chinese Medicine (No. YN2019MJ05); the collaborative innovation project of “Double first class” and High-level University Construction of Guangzhou University of Chinese Medicine (Nos. 2021XK69 and 2021XK08); the Science and Technology Commission of Shanghai Municipality (Nos. 21ZR1474700 and 19XD1404700); and the Youth Innovation Promotion Association of CAS (No. 2022279).