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Discovery of a first-in-class reversible DNMT1-selective inhibitor with improved tolerability and efficacy in acute myeloid leukemia.

Pappalardi MB, Keenan K, Cockerill M, Kellner WA, Stowell A, Sherk C, Wong K, Pathuri S, Briand J, Steidel M, Chapman P, Groy A, Wiseman AK, McHugh CF, Campobasso N, Graves AP, Fairweather E, Werner T, Raoof A, Butlin RJ, Rueda L, Horton JR, Fosbenner DT, Zhang C, Handler JL, Muliaditan M, Mebrahtu M, Jaworski JP, McNulty DE, Burt C, Eberl HC, Taylor AN, Ho T, Merrihew S, Foley SW, Rutkowska A, Li M, Romeril SP, Goldberg K, Zhang X, Kershaw CS, Bantscheff M, Jurewicz AJ, Minthorn E, Grandi P, Patel M, Benowitz AB, Mohammad HP, Gilmartin AG, Prinjha RK, Ogilvie D, Carpenter C, Heerding D, Baylin SB, Jones PA, Cheng X, King BW, Luengo JI, Jordan AM, Waddell I, Kruger RG, McCabe MT
Nat Cancer 2 1002-1017 (2021)
Related entries: 6x9i, 6x9j

Cited: 60 times
EuropePMC logo PMID: 34790902

Abstract

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.

Articles - 6x9k mentioned but not cited (3)

  1. Discovery of a first-in-class reversible DNMT1-selective inhibitor with improved tolerability and efficacy in acute myeloid leukemia. Pappalardi MB, Keenan K, Cockerill M, Kellner WA, Stowell A, Sherk C, Wong K, Pathuri S, Briand J, Steidel M, Chapman P, Groy A, Wiseman AK, McHugh CF, Campobasso N, Graves AP, Fairweather E, Werner T, Raoof A, Butlin RJ, Rueda L, Horton JR, Fosbenner DT, Zhang C, Handler JL, Muliaditan M, Mebrahtu M, Jaworski JP, McNulty DE, Burt C, Eberl HC, Taylor AN, Ho T, Merrihew S, Foley SW, Rutkowska A, Li M, Romeril SP, Goldberg K, Zhang X, Kershaw CS, Bantscheff M, Jurewicz AJ, Minthorn E, Grandi P, Patel M, Benowitz AB, Mohammad HP, Gilmartin AG, Prinjha RK, Ogilvie D, Carpenter C, Heerding D, Baylin SB, Jones PA, Cheng X, King BW, Luengo JI, Jordan AM, Waddell I, Kruger RG, McCabe MT. Nat Cancer 2 1002-1017 (2021)
  2. Structural characterization of dicyanopyridine containing DNMT1-selective, non-nucleoside inhibitors. Horton JR, Pathuri S, Wong K, Ren R, Rueda L, Fosbenner DT, Heerding DA, McCabe MT, Pappalardi MB, Zhang X, King BW, Cheng X. Structure 30 793-802.e5 (2022)
  3. Discovery of potent DNMT1 inhibitors against sickle cell disease using structural-based virtual screening, MM-GBSA and molecular dynamics simulation-based approaches. Ala C, Joshi RP, Gupta P, Ramalingam S, Sankaranarayanan M. J Biomol Struct Dyn 1-13 (2023)


Reviews citing this publication (21)

  1. An Epigenetic Role of Mitochondria in Cancer. Liu Y, Chen C, Wang X, Sun Y, Zhang J, Chen J, Shi Y. Cells 11 2518 (2022)
  2. Differentiation therapy for myeloid malignancies: beyond cytotoxicity. Stubbins RJ, Karsan A. Blood Cancer J 11 193 (2021)
  3. Generating specificity in genome regulation through transcription factor sensitivity to chromatin. Isbel L, Grand RS, Schübeler D. Nat Rev Genet 23 728-740 (2022)
  4. Exploiting RIG-I-like receptor pathway for cancer immunotherapy. Jiang Y, Zhang H, Wang J, Chen J, Guo Z, Liu Y, Hua H. J Hematol Oncol 16 8 (2023)
  5. Targeting DNA Methylation in Leukemia, Myelodysplastic Syndrome, and Lymphoma: A Potential Diagnostic, Prognostic, and Therapeutic Tool. Kalinkova L, Sevcikova A, Stevurkova V, Fridrichova I, Ciernikova S. Int J Mol Sci 24 633 (2022)
  6. Enzyme-free targeted DNA demethylation using CRISPR-dCas9-based steric hindrance to identify DNA methylation marks causal to altered gene expression. Sapozhnikov DM, Szyf M. Nat Protoc 17 2840-2881 (2022)
  7. Epigenetic regulation in hematopoiesis and its implications in the targeted therapy of hematologic malignancies. Zhao A, Zhou H, Yang J, Li M, Niu T. Signal Transduct Target Ther 8 71 (2023)
  8. DNA methyltransferase-1 in acute myeloid leukaemia: beyond the maintenance of DNA methylation. Li M, Zhang D. Ann Med 54 2011-2023 (2022)
  9. The Multi-Omic Landscape of Primary Breast Tumors and Their Metastases: Expanding the Efficacy of Actionable Therapeutic Targets. Yang G, Lu T, Weisenberger DJ, Liang G. Genes (Basel) 13 1555 (2022)
  10. Bidirectional interplay between metabolism and epigenetics in hematopoietic stem cells and leukemia. Zhang YW, Schönberger K, Cabezas-Wallscheid N. EMBO J 42 e112348 (2023)
  11. Epigenetic Regulators of DNA Cytosine Modification: Promising Targets for Cancer Therapy. Jung I, An J, Ko M. Biomedicines 11 654 (2023)
  12. Epigenetics in Pancreatic Ductal Adenocarcinoma: Impact on Biology and Utilization in Diagnostics and Treatment. Elrakaybi A, Ruess DA, Lübbert M, Quante M, Becker H. Cancers (Basel) 14 5926 (2022)
  13. Large-Scale Chromatin Rearrangements in Cancer. Yamaguchi K, Chen X, Oji A, Hiratani I, Defossez PA. Cancers (Basel) 14 2384 (2022)
  14. DNA Methylation in Alcohol Use Disorder. Zheng Q, Wang H, Yan A, Yin F, Qiao X. Int J Mol Sci 24 10130 (2023)
  15. Inhibitors of DNA Methylation. Lopez M, Gilbert J, Contreras J, Halby L, Arimondo PB. Adv Exp Med Biol 1389 471-513 (2022)
  16. Mediating and maintaining methylation while minimizing mutation: Recent advances on mammalian DNA methyltransferases. Cheng X, Blumenthal RM. Curr Opin Struct Biol 75 102433 (2022)
  17. Methylation across the central dogma in health and diseases: new therapeutic strategies. Liu R, Zhao E, Yu H, Yuan C, Abbas MN, Cui H. Signal Transduct Target Ther 8 310 (2023)
  18. Minor structural changes, major functional impacts: posttranslational modifications and drug targets. Kim HJ. Arch Pharm Res 45 693-703 (2022)
  19. Regulation of DNA Methylation by Cannabidiol and Its Implications for Psychiatry: New Insights from In Vivo and In Silico Models. Domingos LB, Silva NR, Chaves Filho AJM, Sales AJ, Starnawska A, Joca S. Genes (Basel) 13 2165 (2022)
  20. Transcriptional and Epigenetic Regulation of Context-Dependent Plasticity in T-Helper Lineages. Friedman MJ, Lee H, Lee JY, Oh S. Immune Netw 23 e5 (2023)
  21. Viewing AML through a New Lens: Technological Advances in the Study of Epigenetic Regulation. Godfrey LC, Rodriguez-Meira A. Cancers (Basel) 14 5989 (2022)

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