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

Melissa B. Pappalardi; Kathryn Keenan; Mark Cockerill; Wendy A. Kellner; Alexandra Stowell; Christian Sherk; Kristen Wong; Sarath Pathuri; Jacques Briand; Michael Steidel; Philip Chapman; Arthur Groy; Ashley K. Wiseman; Charles F. McHugh; Nino Campobasso; Alan P. Graves; Emma Fairweather; Thilo Werner; Ali Raoof; Roger J. Butlin; Lourdes Rueda; John R. Horton; David T. Fosbenner; Cunyu Zhang; Jessica L. Handler; Morris Muliaditan; Makda Mebrahtu; Jon Paul Jaworski; Dean E. McNulty; Charlotte Burt; H. Christian Eberl; Amy N. Taylor; Thau Ho; Susan Merrihew; Shawn W. Foley; Anna Rutkowska; Mei Li; Stuart P. Romeril; Kristin Goldberg; Xing Zhang; Christopher S. Kershaw; Marcus Bantscheff; Anthony J. Jurewicz; Elisabeth Minthorn; Paola Grandi; Mehul Patel; Andrew B. Benowitz; Helai P. Mohammad; Aidan G. Gilmartin; Rab K. Prinjha; Donald Ogilvie; Christopher Carpenter; Dirk Heerding; Stephen B. Baylin; Peter A. Jones; Xiaodong Cheng; Bryan W. King; Juan I. Luengo; Allan M. Jordan; Ian Waddell; Ryan G. Kruger; Michael T. McCabe

doi:10.1038/s43018-021-00249-x

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

Melissa B. Pappalardi, Kathryn Keenan, Mark Cockerill, Wendy A. Kellner, Alexandra Stowell, Christian Sherk, Kristen Wong, Sarath Pathuri, Jacques Briand, Michael Steidel, Philip Chapman, Arthur Groy, Ashley K. Wiseman, Charles F. McHugh, Nino Campobasso, Alan P. Graves, Emma Fairweather, Thilo Werner, Ali Raoof, Roger J. ButlinLourdes Rueda, John R. Horton, David T. Fosbenner, Cunyu Zhang, Jessica L. Handler, Morris Muliaditan, Makda Mebrahtu, Jon Paul Jaworski, Dean E. McNulty, Charlotte Burt, H. Christian Eberl, Amy N. Taylor, Thau Ho, Susan Merrihew, Shawn W. Foley, Anna Rutkowska, Mei Li, Stuart P. Romeril, Kristin Goldberg, Xing Zhang, Christopher S. Kershaw, Marcus Bantscheff, Anthony J. Jurewicz, Elisabeth Minthorn, Paola Grandi, Mehul Patel, Andrew B. Benowitz, Helai P. Mohammad, Aidan G. Gilmartin, Rab K. Prinjha, Donald Ogilvie, Christopher Carpenter, Dirk Heerding, Stephen B. Baylin, Peter A. Jones, Xiaodong Cheng, Bryan W. King, Juan I. Luengo, Allan M. Jordan, Ian Waddell, Ryan G. Kruger, Michael T. McCabe

School of Medicine

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	1002-1017
Number of pages	16
Journal	Nature Cancer
Volume	2
Issue number	10
DOIs	https://doi.org/10.1038/s43018-021-00249-x
State	Published - Oct 2021

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1038/s43018-021-00249-x

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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, 2(10), 1002-1017. https://doi.org/10.1038/s43018-021-00249-x

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 2021, 'Discovery of a first-in-class reversible DNMT1-selective inhibitor with improved tolerability and efficacy in acute myeloid leukemia', Nature Cancer, vol. 2, no. 10, pp. 1002-1017. https://doi.org/10.1038/s43018-021-00249-x

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title = "Discovery of a first-in-class reversible DNMT1-selective inhibitor with improved tolerability and efficacy in acute myeloid leukemia",

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.",

author = "Pappalardi, {Melissa B.} and Kathryn Keenan and Mark Cockerill and Kellner, {Wendy A.} and Alexandra Stowell and Christian Sherk and Kristen Wong and Sarath Pathuri and Jacques Briand and Michael Steidel and Philip Chapman and Arthur Groy and Wiseman, {Ashley K.} and McHugh, {Charles F.} and Nino Campobasso and Graves, {Alan P.} and Emma Fairweather and Thilo Werner and Ali Raoof and Butlin, {Roger J.} and Lourdes Rueda and Horton, {John R.} and Fosbenner, {David T.} and Cunyu Zhang and Handler, {Jessica L.} and Morris Muliaditan and Makda Mebrahtu and Jaworski, {Jon Paul} and McNulty, {Dean E.} and Charlotte Burt and Eberl, {H. Christian} and Taylor, {Amy N.} and Thau Ho and Susan Merrihew and Foley, {Shawn W.} and Anna Rutkowska and Mei Li and Romeril, {Stuart P.} and Kristin Goldberg and Xing Zhang and Kershaw, {Christopher S.} and Marcus Bantscheff and Jurewicz, {Anthony J.} and Elisabeth Minthorn and Paola Grandi and Mehul Patel and Benowitz, {Andrew B.} and Mohammad, {Helai P.} and Gilmartin, {Aidan G.} and Prinjha, {Rab K.} and Donald Ogilvie and Christopher Carpenter and Dirk Heerding and Baylin, {Stephen B.} and Jones, {Peter A.} and Xiaodong Cheng and King, {Bryan W.} and Luengo, {Juan I.} and Jordan, {Allan M.} and Ian Waddell and Kruger, {Ryan G.} and McCabe, {Michael T.}",

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year = "2021",

month = oct,

doi = "10.1038/s43018-021-00249-x",

language = "English (US)",

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T1 - Discovery of a first-in-class reversible DNMT1-selective inhibitor with improved tolerability and efficacy in acute myeloid leukemia

AU - Pappalardi, Melissa B.

AU - Keenan, Kathryn

AU - Cockerill, Mark

AU - Kellner, Wendy A.

AU - Stowell, Alexandra

AU - Sherk, Christian

AU - Wong, Kristen

AU - Pathuri, Sarath

AU - Briand, Jacques

AU - Steidel, Michael

AU - Chapman, Philip

AU - Groy, Arthur

AU - Wiseman, Ashley K.

AU - McHugh, Charles F.

AU - Campobasso, Nino

AU - Graves, Alan P.

AU - Fairweather, Emma

AU - Werner, Thilo

AU - Raoof, Ali

AU - Butlin, Roger J.

AU - Rueda, Lourdes

AU - Horton, John R.

AU - Fosbenner, David T.

AU - Zhang, Cunyu

AU - Handler, Jessica L.

AU - Muliaditan, Morris

AU - Mebrahtu, Makda

AU - Jaworski, Jon Paul

AU - McNulty, Dean E.

AU - Burt, Charlotte

AU - Eberl, H. Christian

AU - Taylor, Amy N.

AU - Ho, Thau

AU - Merrihew, Susan

AU - Foley, Shawn W.

AU - Rutkowska, Anna

AU - Li, Mei

AU - Romeril, Stuart P.

AU - Goldberg, Kristin

AU - Zhang, Xing

AU - Kershaw, Christopher S.

AU - Bantscheff, Marcus

AU - Jurewicz, Anthony J.

AU - Minthorn, Elisabeth

AU - Grandi, Paola

AU - Patel, Mehul

AU - Benowitz, Andrew B.

AU - Mohammad, Helai P.

AU - Gilmartin, Aidan G.

AU - Prinjha, Rab K.

AU - Ogilvie, Donald

AU - Carpenter, Christopher

AU - Heerding, Dirk

AU - Baylin, Stephen B.

AU - Jones, Peter A.

AU - Cheng, Xiaodong

AU - King, Bryan W.

AU - Luengo, Juan I.

AU - Jordan, Allan M.

AU - Waddell, Ian

AU - Kruger, Ryan G.

AU - McCabe, Michael T.

PY - 2021/10

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N2 - 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.

AB - 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.

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

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