Treating Hematological Malignancies With OR-2100, an Orally Bioavailable Prodrug of Decitabine

Abstract

DNA methylation is an enzyme-driven epigenetic modification that must be precisely regulated to maintain cellular homeostasis. Aberrant methylation status, especially hypermethylation of the promoter sites of tumor-suppressor genes, is observed in human malignancies and is a proven target for cancer therapy. The first-generation DNA demethylating agents, azacitidine and decitabine, are widely used for treating several hematological malignancies. In addition, orally bioavailable prodrugs of azacitidine and decitabine have recently been approved by the FDA. We have developed a silylated derivative of decitabine, OR-2100, which is resistant to degradation by cytidine deaminase and orally bioavailable. It has efficacy against several human hematological malignancies in xenograft mouse models with less hematotoxicity than decitabine. Since DNA demethylating agents are combined with molecularly targeted drugs in clinical use and trials, we think that the less hematotoxic profile of OR-2100 makes it suitable for use as a combination therapy. In this article, we review the therapeutic approach in hematological malignancies with the DNA demethylating agent OR-2100.

Keywords: DNA demethylating agents; DNA methylation; combination therapy; hematological malignancies; prodrug.

FIGURE 1

Metabolic pathway of azacitidine (AZA) and decitabine (DAC). AZA and DAC undergo multi‐step phosphorylation and are incorporated into DNA and RNA. DAC incorporates into DNA more efficiently than AZA, resulting in DNA hypomethylation via DNMT1 depletion.

FIGURE 2

Leukemogenesis in adult T‐cell leukemia/lymphoma. Most HTLV‐1‐infected individuals remain asymptomatic throughout their lives, but 2%–5% develop ATL with a long latency period, and 50% of patients with indolent ATL, such as smoldering and chronic type of ATL, progress to aggressive ATL within several decades. The development and progression of ATL are associated with aberrant regional DNA hypermethylation in HTLV‐1 infected cells that is linked to the emergence and expansion of ATL cells.

FIGURE 3

OR‐2100 prevents leukemogenesis associated with aberrant DNA methylation in AKR mice. Tumor cells isolated from AKR mice have hypermethylated proximal promoter regions compared with normal T cells (left panel). Kaplan–Meier survival curves of AKR mice treated with vehicle, OR‐2100 or DAC (right panel) [46]. Part of material from: Yuta Yamamoto et al., DNA demethylating agents for chemoprevention of oncovirus‐associated leukemogenesis, Leukemia, 2024, Springer Nature.