3‐Deazaneplanocin A and Neplanocin A Analogues and Their Effects on Apoptotic Cell Death

Abstract

3-Deazaneplanocin A (DzNep) is a potential epigenetic drug for the treatment of various cancers. DzNep has been reported to deplete histone methylations, including oncogenic EZH2 complex, giving rise to epigenetic modifications that reactivate many silenced tumor suppressors in cancer cells. Despite its promise as an anticancer drug, little is known about the structure-activity relationships of DzNep in the context of epigenetic modifications and apoptosis induction. In this study, a number of analogues of DzNep were examined for DzNep-like ability to induce synergistic apoptosis in cancer cells in combination with trichostatin A, a known histone deacetylase (HDAC) inhibitor. The structure-activity relationship data thus obtained provide valuable information on the structural requirements for biological activity. The studies identified three compounds that show similar activities to DzNep. Two of these compounds show good pharmacokinetics and safety profiles. Attempts to correlate the observed synergistic apoptotic activities with measured S-adenosylhomocysteine hydrolase (SAHH) inhibitory activities suggest that the apoptotic activity of DzNep might not be directly due to its inhibition of SAHH.

A Proof-of-Concept for Epigenetic Therapy of Tissue Fibrosis: Inhibition of Liver Fibrosis Progression by 3-Deazaneplanocin A

“…DZNep is a purine nucleoside analog (PNA), which is in a family of compounds, many of which are being used clinically and have been proven to be effective in the treatment of hematological malignancies and autoimmune disorders 33 . In a blinded fashion, we began by determining the ability of several chemically-related PNAs (designated compounds 1–9; Figure S1) to inhibit HSC expression of transcripts for the profibrogenic genes collagen 1A1, αSMA, and TIMP-1.…”

Identification of inhibitors of myeloid-derived suppressor cells activity through phenotypic chemical screening

“…Not surprisingly, the inhibition of DNA methyltransferase activity by DZNep has been shown to have pleiotropic effects on anti-tumor responses as reported by several independent studies. 46,47,58,59 5-aza-2-deoxycytidine (5-AZA-dC) and DZNep have been shown to improve anti-tumor response by increasing CXCL9 and CXCL10 expression in cancer cells and tumor infiltration by T cells 60 or by inducing type I or III interferon responses through reactivation of endogenous retrovirus transcription. 61,62 On the other hand, EZH2 deletion or inhibition has been reported to negatively impact cytokine production and T cell survival.…”

“…45 It induces accumulation of S-adenosyl-L-homocysteine, a by-product of S-adenosyl methionine (SAM)-dependent methylation, thereby, inhibiting methyltransferases. 45,46 It has also been shown to deplete EZH2 levels, thereby, inhibiting trimethylation of lysine 27 on histone H3 by blocking the polycomb-repressive-complex 2 in primary AML cells in a dose-dependent manner (0.2-1 mM). 47,48 Although both RA and DZNep inhibit MDSC suppressive functions, they did so in a qualitative and quantitative different manner ( Fig.…”

Preclinical pharmacokinetic studies of 3-deazaneplanocin A, a potent epigenetic anticancer agent, and its human pharmacokinetic prediction using GastroPlus™

“…However, due to the unfavorable plasma pharmacokinetic (PK) properties of DZNep (half-life of 1.1 h in rats and 0.9 h in mice) (Peer et al, 2013;Sun et al, 2012), the antitumor studies on DZNep have been stuck in the preclinical phase. In order to ameliorate its plasma PK properties, recent efforts have led to the advent of novel nanoparticle carriers or analogous (Hung et al, 2013;Sun et al, 2012;Tam et al, 2015). Unfortunately, the pharmacological effects of the new formulations or analogues on cancer cell death or EZH2 modulation were not comparable to DZNep.…”