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Structural Investigations of Phthalazinone Derivatives as Allosteric Inhibitors of Human DNA Methyltransferase 3A
The development of new therapeutics targeting enzymes involved in epigenetic pathways such as histone modification and DNA methylation has received a lot of attention, particularly for targeting diverse cancers. Unfortunately, irreversible nucleoside inhibitors (azacytidine and decitabine) have prov...
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Published in: | ACS medicinal chemistry letters 2024-05, Vol.15 (5), p.590-594 |
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Main Authors: | , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites |
Online Access: | Get full text |
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Summary: | The development of new therapeutics targeting enzymes involved in epigenetic pathways such as histone modification and DNA methylation has received a lot of attention, particularly for targeting diverse cancers. Unfortunately, irreversible nucleoside inhibitors (azacytidine and decitabine) have proven highly cytotoxic, and competitive inhibitors are also problematic. This work describes synthetic and structural investigations of a new class of allosteric DNA methyltransferase 3A (DNMT3A) inhibitors, leading to the identification of several critical pharmacophores in the lead structure. Specifically, we find that the tetrazole and phthalazinone moieties are indispensable for the inhibitory activity of DNMT3A and elucidate other modifiable regions in the lead compound. |
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ISSN: | 1948-5875 1948-5875 |
DOI: | 10.1021/acsmedchemlett.3c00528 |