The DOI matches its Crossref record; 65 of the 65 references it cites were found in a registry or an index.
Discovery of a first-in-class reversible DNMT1-selective inhibitor with improved tolerability and efficacy in acute myeloid leukemia
Open accessAbstract
DNA methylation, a key epigenetic driver of transcriptional silencing, is universally dysregulated in cancer. Reversal of DNA methylation by hypomethylating agents, such as the cytidine analogs decitabine or azacytidine, has demonstrated clinical benefit in hematologic malignancies. These nucleoside analogs are incorporated into replicating DNA where they inhibit DNA cytosine methyltransferases DNMT1, DNMT3A and DNMT3B through irreversible covalent interactions. These agents induce notable toxicity to normal blood cells thus limiting their clinical doses. Herein we report the discovery of GSK3685032, a potent first-in-class DNMT1-selective inhibitor that was shown via crystallographic studies to compete with the active-site loop of DNMT1 for penetration into hemi-methylated DNA between two CpG base pairs. GSK3685032 induces robust loss of DNA methylation, transcriptional activation and cancer cell growth inhibition in vitro. Due to improved in vivo tolerability compared with decitabine, GSK3685032 yields superior tumor regression and survival mouse models of acute myeloid leukemia. Pappalardi and colleagues identify a potent noncovalent DNMT1-selective inhibitor with improved tolerability and efficacy in preclinical AML models compared with clinically validated covalent pan-DNMT inhibitors.
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Self-citationDynamic STING repression orchestrates immune cell development and function
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DNA methylation protects cancer cells against senescence
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Metadata
- Authors
- Pappalardi, M. B., Keenan, K., Cockerill, M., Kellner, W. A., Stowell, A., Sherk, C., Wong, K., Pathuri, S., Briand, J., Steidel, M., Chapman, P., Groy, A., Wiseman, A. K., McHugh, C. F., Campobasso, N., Graves, A. P., Fairweather, E., Werner, T., Raoof, A., Butlin, R. J., Rueda, L., Horton, J. R., Fosbenner, D. T., Zhang, C., Handler, J. L., Muliaditan, M., Mebrahtu, M., Jaworski, J.-P., McNulty, D. E., Burt, C., Eberl, H. C., Taylor, A. N., Ho, T., Merrihew, S., Foley, S. W., Rutkowska, A., Li, M., Romeril, S. P., Goldberg, K., Zhang, X., Kershaw, C. S., Bantscheff, M., Jurewicz, A. J., Minthorn, E., Grandi, P., Patel, M., Benowitz, A. B., Mohammad, H. P., Gilmartin, A. G., Prinjha, R. K., Ogilvie, D., Carpenter, C., Heerding, D., Baylin, S. B., Jones, P. A., Cheng, X., King, B. W., Luengo, J. I., Jordan, A. M., Waddell, I., Kruger, R. G., & McCabe, M. T.
- Venue
- Nature Cancer
- Published
- 2021-09-27
- Volume
- 2
- Issue
- 10
- Pages
- 1002-1017
- ISSN
- 2662-1347 (ISSN-L)
- OpenAlex
- W3202606175
- Cited by
- 283
- References
- 65
- FWCI
- 11.20
- Type
- journal article
- Language
- en
- Open access
- green
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- CoChat. (2026). Citation check: Discovery of a first-in-class reversible DNMT1-selective inhibitor with improved tolerability and efficacy in acute myeloid leukemia. https://app.cochat.ai/papers/10.1038/s43018-021-00249-x
- The paper
- Pappalardi, M. B., Keenan, K., Cockerill, M., Kellner, W. A., Stowell, A., Sherk, C., Wong, K., Pathuri, S., Briand, J., Steidel, M., Chapman, P., Groy, A., Wiseman, A. K., McHugh, C. F., Campobasso, N., Graves, A. P., Fairweather, E., Werner, T., Raoof, A., . . . McCabe, M. T. (2021). Discovery of a first-in-class reversible DNMT1-selective inhibitor with improved tolerability and efficacy in acute myeloid leukemia. Nature Cancer. https://doi.org/10.1038/s43018-021-00249-x
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
