Silylation of Deoxynucleotide Analog Yields an Orally Available Drug with Antileukemia Effects

Abstract

DNA methyltransferase inhibitors have improved the prognosis of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, because these agents are easily degraded by cytidine deaminase (CDA), they must be administered intravenously or subcutaneously. Recently, two orally bioavailable DNA methyltransferase inhibitors, CC-486 and ASTX727, were approved. In previous work, we developed 5-O-trialkylsilylated decitabines that resist degradation by CDA.However, the effects of silylation of a deoxynucleotide analog and enzymatic cleavage of silylation have not been fully elucidated. Enteric administration of OR21 in a cynomolgus monkey model led to high plasma concentrations and hypomethylation, and in a mouse model, oral administration of enteric-coated OR21 led to high plasma concentrations. The drug became biologically active after release of decitabine (DAC) from OR21 following removal of the 5'-O-trisilylate substituent. Toxicities were tolerable and lower than those of DAC. Transcriptome and methylome analysis of MDS and AML cell lines revealed that OR21 increased expression of genes associated with tumor suppression, cell differentiation, and immune system processes by altering regional promoter methylation, indicating that these pathways play pivotal roles in the action of hypomethylating agents. OR21 induced cell differentiation via upregulation of the late cell differentiation drivers CEBPE and GATA-1. Thus, silylation of a deoxynucleotide analog can confer oral bioavailability without new toxicities. Both in vivo and in vitro, OR21 exerted anti-leukemia effects, and had a better safety profile

Combination of a New Oral Demethylating Agent, OR2100, and Venetoclax for Treatment of Acute Myeloid Leukemia

“…Similar to DAC ( 11 ), OR21 monotherapy inhibited growth of AML cell lines (HL60, SKM1, THP1, KG1a, and Kasumi-1) in a dose-dependent manner ( Supplementary Fig. S1 ).…”

“…Thus, we did not test the DAC plus Ven in vivo . Moreover, OR21 is an effective treatment for AZA-resistant leukemia in vi vo ( 11, 30 ). Hence, the combination of Ven plus OR21 may benefit patients with AML, including AZA-resistant AML, thereby replacing the standard therapy.…”

“…The intraperitoneal route was used because OR21 is easily degraded by gastric acid. Gelatin capsules filled with enteric-coated granules of OR21 were prepared and oral availability was confirmed in cynomolgus monkeys, as described previously ( 11 ); however, the granules were too large to administer to mice. Mice were observed daily and euthanized when they showed signs of progressive disease, including hind limb paralysis, >20% weight loss, or lethargy.…”

Dual targeting of aberrant DNA and histone methylation synergistically suppresses tumor cell growth in ATL

“…Although combination therapy is often associated with side effects, we demonstrated that the hematotoxicity of combination treatment with OR21 and EZH2 was not greater than that of single treatment ( Figure 6 D). OR21 has lower hematotoxicity than DAC, 24 , 25 , 26 suggesting that a combination with OR21 rather than DAC could be clinically beneficial.…”

“… 24 OR21 is a silylated derivative of DAC that is resistant to cytidine deaminase and can be administered orally. 24 , 25 , 26 These previous results led us to investigate the effect of combination treatment with DNA demethylating agents and EZH2 inhibitors in patients with ATL.…”