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

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

  • Nat Cancer. 2021 Oct;2(10):1002-1017.
Melissa B Pappalardi 1,  Kathryn Keenan 1,  Mark Cockerill 2 3,  Wendy A Kellner 1 3,  Alexandra Stowell 2,  Christian Sherk 1,  Kristen Wong 1,  Sarath Pathuri 4,  Jacques Briand 5,  Michael Steidel 6,  Philip Chapman 2,  Arthur Groy 7,  Ashley K Wiseman 8,  Charles F McHugh 1,  Nino Campobasso 5,  Alan P Graves 5,  Emma Fairweather 2,  Thilo Werner 6,  Ali Raoof 2,  Roger J Butlin 2,  Lourdes Rueda 1,  John R Horton 4,  David T Fosbenner 1,  Cunyu Zhang 1,  Jessica L Handler 1,  Morris Muliaditan 9,  Makda Mebrahtu 5,  Jon-Paul Jaworski 5,  Dean E McNulty 5,  Charlotte Burt 2,  H Christian Eberl 6,  Amy N Taylor 5,  Thau Ho 5,  Susan Merrihew 1,  Shawn W Foley 1,  Anna Rutkowska 6,  Mei Li 1,  Stuart P Romeril 1,  Kristin Goldberg 2,  Xing Zhang 4,  Christopher S Kershaw 2,  Marcus Bantscheff 6,  Anthony J Jurewicz 5,  Elisabeth Minthorn 1,  Paola Grandi 6,  Mehul Patel 5,  Andrew B Benowitz 7,  Helai P Mohammad 1,  Aidan G Gilmartin 7,  Rab K Prinjha 1,  Donald Ogilvie 2,  Christopher Carpenter 1,  Dirk Heerding 1,  Stephen B Baylin 10,  Peter A Jones 8,  Xiaodong Cheng 4,  Bryan W King 1,  Juan I Luengo 1,  Allan M Jordan 2,  Ian Waddell 2,  Ryan G Kruger 1,  Michael T McCabe 1
Affiliations

Affiliations

  • 1 Cancer Epigenetics Research Unit, Oncology, GlaxoSmithKline, Collegeville, PA, USA.
  • 2 Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield, UK.
  • 3 These authors contributed equally: Mark Cockerill, Wendy A. Kellner.
  • 4 Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5 Medicinal Science & Technology, GlaxoSmithKline, Collegeville, PA, USA.
  • 6 Cellzome GmbH, Functional Genomics, GlaxoSmithKline, Heidelberg, Germany.
  • 7 Future Pipeline Discovery, GlaxoSmithKline, Collegeville, PA, USA.
  • 8 Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI, USA.
  • 9 Drug Metabolism and Pharmacokinetics Modelling, GlaxoSmithKline, Stevenage, UK.
  • 10 Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
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.

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