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Silylation of Deoxynucleotide Analog Yields an Orally Available Drug with Anti-Leukemia Effects

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Silylation of Deoxynucleotide Analog Yields an Orally Available Drug with Anti-Leukemia Effects Author Manuscript Published OnlineFirst on May 27, 2021; DOI: 10.1158/1535-7163.MCT-20-1125 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Ureshino et al. Silylation of DAC for MDS and AML. 1 Original article 2 Silylation of deoxynucleotide analog yields an orally available drug 3 with anti-leukemia effects 4 5 Hiroshi Ureshino1,2†, Yuki Kurahashi1†, Tatsuro Watanabe1, Satoshi Yamashita3, 6 Kazuharu Kamachi1,2, Yuta Yamamoto1, Yuki Fukuda-Kurahashi1, Nao 7 Yoshida-Sakai1,2, Naoko Hattori3, Yoshihiro Hayashi4, Atsushi Kawaguchi5, Kaoru 8 Tohyama6, Seiji Okada7, Hironori Harada4, Toshikazu Ushijima3, and Shinya Kimura1, 9 2* 10 11 † These authors equally contributed to this work. 12 13 1Department of Drug Discovery and Biomedical Sciences, Faculty of Medicine, Saga 14 University, Saga, Japan; 2Division of Hematology, Respiratory Medicine and Oncology, 15 Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan; 16 3Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan; 17 4Laboratory of Oncology, School of Life Sciences, Tokyo University of Pharmacy and 18 Life Sciences, Tokyo, Japan; 5Center for Comprehensive Community Medicine, Faculty 19 of Medicine Saga University, Saga, Japan; 6Department of Laboratory Medicine, 20 Kawasaki Medical School, Kurashiki, Japan; 7Division of Hematopoiesis, Joint 21 Research Center for Human Retrovirus Infection, Kumamoto, Japan. 22 23 *Corresponding author: Shinya Kimura, MD, PhD 24 5-1-1 Nabeshima, Saga 849-8501, Japan 25 Phone: +81-952-34-2366, Fax: +81-952-34-2017 26 E-mail: [email protected] 1 Downloaded from mct.aacrjournals.org on October 1, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 27, 2021; DOI: 10.1158/1535-7163.MCT-20-1125 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Ureshino et al. Silylation of DAC for MDS and AML. 27 Conflict-of-interest disclosure: This work was supported by Ohara Pharmaceutical. 28 29 Running title: Silylation of DAC for MDS and AML 30 Main text: 4115 words 31 Abstract: 248 words 32 Figures: 6 33 References: 50 34 Supplementary figure, 16; Tables, 4; method, 1 35 Supplementary figure only for reviewers: 1 36 2 Downloaded from mct.aacrjournals.org on October 1, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 27, 2021; DOI: 10.1158/1535-7163.MCT-20-1125 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Ureshino et al. Silylation of DAC for MDS and AML. 37 Abstract 38 DNA methyltransferase inhibitors have improved the prognosis of myelodysplastic 39 syndrome (MDS) and acute myeloid leukemia (AML). However, because these agents 40 are easily degraded by cytidine deaminase (CDA), they must be administered 41 intravenously or subcutaneously. Recently, two orally bioavailable DNA 42 methyltransferase inhibitors, CC-486 and ASTX727, were approved. In previous work, 43 we developed 5-O-trialkylsilylated decitabines that resist degradation by CDA. 44 However, the effects of silylation of a deoxynucleotide analog and enzymatic cleavage 45 of silylation have not been fully elucidated. Enteric administration of OR21 in a 46 cynomolgus monkey model led to high plasma concentrations and hypomethylation, 47 and in a mouse model, oral administration of enteric-coated OR21 led to high plasma 48 concentrations. The drug became biologically active after release of decitabine (DAC) 49 from OR21 following removal of the 5'-O-trisilylate substituent. Toxicities were 50 tolerable and lower than those of DAC. Transcriptome and methylome analysis of MDS 51 and AML cell lines revealed that OR21 increased expression of genes associated with 52 tumor suppression, cell differentiation, and immune system processes by altering 53 regional promoter methylation, indicating that these pathways play pivotal roles in the 54 action of hypomethylating agents. OR21 induced cell differentiation via upregulation of 55 the late cell differentiation drivers CEBPE and GATA-1. Thus, silylation of a 56 deoxynucleotide analog can confer oral bioavailability without new toxicities. Both in 57 vivo and in vitro, OR21 exerted anti-leukemia effects, and had a better safety profile 3 Downloaded from mct.aacrjournals.org on October 1, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 27, 2021; DOI: 10.1158/1535-7163.MCT-20-1125 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Ureshino et al. Silylation of DAC for MDS and AML. 58 than DAC. Together, our findings indicate that OR21 is a promising candidate drug for 59 phase 1 study as an alternative to azacitidine or decitabine. 60 Keywords: silylation, hypomethylating, orally available, OR-2100, myelodysplastic 61 syndrome, acute myeloid leukemia 62 4 Downloaded from mct.aacrjournals.org on October 1, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 27, 2021; DOI: 10.1158/1535-7163.MCT-20-1125 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Ureshino et al. Silylation of DAC for MDS and AML. 63 Introduction 64 Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are 65 characterized by impaired differentiation of hematopoietic stem cells (HSCs) or 66 hematopoietic progenitor cells (1,2). Somatic mutations and aberrant DNA 67 hypermethylation that silence cancer-regulating genes (e.g., tumor-suppressor genes) in 68 these cells (3) are involved in pathogenesis and progression of MDS and AML (4–8). 69 Epigenetic alterations lead to reduced hypermethylation, which can in turn cause 70 re-expression of silenced tumor-regulating genes. These alterations represent novel 71 therapeutic targets for both of these cancers (9). 72 Although the clinically available DNA methyltransferase (DNMT) inhibitors 73 azacitidine (AZA) and decitabine (DAC) have improved the prognosis of MDS and 74 AML (10,11), they are easily degraded by cytidine deaminase (CDA), limiting their 75 bioavailability after oral administration; consequently, they must be administered 76 intravenously or subcutaneously. The efficacy and safety of oral AZA or DAC, as well 77 as the combination of these drugs with CDA inhibitors, has been evaluated in clinical 78 trials (12–14), resulting in the approval of CC-486 (oral AZA) and ASTX727 (DAC 79 plus cedazuridine, a CDA inhibitor) (13,14). 80 Resistance to CDA is crucial for achieving elevated plasma concentrations of these 81 drugs, which would in turn increase efficacy (15). Silylation of glycoproteins is known 82 to influence their stabilities and therapeutic effects (16,17); however, the effects of 83 silylation of deoxynucleotide analogs and enzymatic cleavage of silylation have not 84 been fully elucidated. In previous work, we developed 5-O-trialkylsilylated DACs that 5 Downloaded from mct.aacrjournals.org on October 1, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 27, 2021; DOI: 10.1158/1535-7163.MCT-20-1125 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Ureshino et al. Silylation of DAC for MDS and AML. 85 were resistant to CDA and exerted anti-cancer effects against solid tumors and adult 86 T-cell leukemia/lymphoma (18,19). In this study, we assessed the oral bioavailability 87 and efficacy of 5-O-trialkylsilylated DAC for treatment of MDS and AML both in vitro 88 and in vivo. 89 90 Materials and methods 91 Reagents 92 5-O-trialkylsilylated DAC (OR2100, 2003, 2007, 2008, 2009, 2010, 2102, 2103, 2104, 93 and 2201) was obtained from Ohara Pharmaceutical (Shiga, Japan). AZA and DAC 94 were purchased from Sigma-Aldrich (St. Louis, MO, USA). All reagents were dissolved 95 in dimethylsulfoxide (DMSO) and stored at -20°C. 96 97 Pharmacokinetic (PK) studies in cynomolgus monkeys and mice 98 All procedures were performed at NISSEI BILIS. The study was compliant with Ohara 99 Pharmaceutical policies on bioethics in animal work, and all procedures were compliant 100 with the relevant national and international guidelines for the care and use of 101 experimental animals. Procedures for PK studies are described in Supplementary 102 methods. 103 104 Cell lines and cultures 105 The MDS-L cell line was derived from the non-leukemic phase of a patient with MDS 106 with refractory anemia-ringed sideroblasts (20). SKM1 cells (derived from the blast 6 Downloaded from mct.aacrjournals.org on October 1, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 27, 2021; DOI: 10.1158/1535-7163.MCT-20-1125 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Ureshino et al. Silylation of DAC for MDS and AML. 107 cells of a patient with MDS) were purchased from the Japanese Collection of Research 108 Bioresources Cell Bank (Osaka, Japan). HL60, THP-1, KG1a, and Kasumi-1 cell lines 109 (derived from AML patients) were purchased from the American Type Culture 110 Collection (Rockville, MD, USA). AZA-resistant HL60 (HL60R) cells were established. 111 Detailed cell culture methods are described in Supplementary methods. 112 113 Primary patient samples 114 Primary samples were obtained from patients with MDS or AML. Experiments were 115 approved by the Institutional Review Board of Saga University, and all procedures 116 involving human participants were undertaken in accordance with the principles of the 117 Declaration of Helsinki. 118 119 Western blot analysis 120 Western blot analyses were performed to assess the protein levels of DNMT1, UCK1, 121 UCK2, and DCK. Procedures are described in Supplementary methods. 122 123 Pyrosequencing assay of long interspersed nucleotide element-1 (LINE-1) and the 124 globin promoter methylations 125 Pyrosequencing assays of LINE-1 methylation were performed to assess global 126 methylation (19). Procedures are described in Supplementary methods.
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