YM753, a novel histone deacetylase inhibitor, exhibits antitumor activity with selective, sustained accumulation of acetylated histones in tumors in the WiDr xenograft model

Abstract

Histone deacetylase (HDAC) inhibitors have been shown to have antitumor activity in vitro and in vivo. Various studies related to their antitumor activity and mechanism of action have been reported for HDAC inhibitors, but the relationship of their antitumor effects to their pharmacodynamic and pharmacokinetic properties in vivo has not ever fully characterized. We report here the discovery of a novel cyclic-peptide-based HDAC inhibitor, YM753. YM753 is a bacteria-derived natural product containing a disulfide bond. It potently inhibited HDAC enzyme with an IC 50 of 2.0 nM in the presence of dithiothreitol. YM753 was rapidly converted to a reduced form in tumor cells, and then induced accumulation of acetylated histones, followed by p21 WAF1/Cip1 expression, tumor cell growth inhibition and tumor-selective cell death. In an in vitro washout study, YM753 showed prolonged accumulation of acetylated histones in WiDr human colon carcinoma cells. In vivo YM753 dosing of mice harboring WiDr colon tumor xenografts significantly inhibited the tumor growth via sustained accumulation of acetylated histones in the tumor tissue. In a pharmacokinetic study, YM753 rapidly disappeared from the plasma, but its reduced form remained in the tumor tissue. Moreover, the accumulation of acetylated histones induced by YM753 was tumor tissue selective compared to several normal tissues. This study provides evidence that YM753 has antitumor activity that is the result of selective, sustained accumulation of acetylated histones in tumor tissues despite rapid disappearance of the drug from the plasma. These results suggest that the novel HDAC inhibitor, YM753 has attractive pharmacodynamic and pharmacokinetic properties giving it potential as an antitumor agent.

A novel HDAC inhibitor OBP-801 and a PI3K inhibitor LY294002 synergistically induce apoptosis via the suppression of survivin and XIAP in renal cell carcinoma

“…We identified OBP-801, also known as YM753, as a novel HDAC inhibitor with attractive pharmacodynamic and pharmacokinetic properties by screening for a p21 WAF1/Cip1 -inducing agent (9). OBP-801 exerted the most potent HDAC-inhibitory activity tested; it was about 50 times more effective than SAHA, the most clinically used HDAC inhibitor (9).…”

A Histone Deacetylase Inhibitor, OBP-801, and Celecoxib Synergistically Inhibit the Cell Growth with Apoptosis via a DR5-Dependent Pathway in Bladder Cancer Cells

“…Several studies have reported that HDAC inhibitors synergize with cisplatin (8) or gemcitabine (9) and could potentially increase clinical efficacy in bladder cancer (10). We previously reported that OBP-801/ YM753, identified as a novel HDAC inhibitor by screening for p21 WAF1/Cip1 -inducing agents, had attractive pharmacodynamic and pharmacokinetic properties (11). OBP-801 exerted the most potent HDAC-inhibitory activity when compared with other HDAC inhibitors (11).…”

“…We previously reported that OBP-801/ YM753, identified as a novel HDAC inhibitor by screening for p21 WAF1/Cip1 -inducing agents, had attractive pharmacodynamic and pharmacokinetic properties (11). OBP-801 exerted the most potent HDAC-inhibitory activity when compared with other HDAC inhibitors (11).…”

HTP Nutraceutical Screening for Histone Deacetylase Inhibitors and Effects of HDACis on Tumor-suppressing miRNAs by Trichostatin A and Grapeseed (Vitis vinifera) in HeLa cells

“…At least 12 different HDACis are currently in use for clinical trials, and more are being sought to augment chemotherapy (4, 5, 7), immunotherapy/ cancer vaccines (14) and overcome multi-drug resistance which are common to diverse cytostatic or receptor-mediated drugs (3,8,9,(36)(37)(38) HDAC inhibitors were first isolated from microorganisms, and continue to be developed from microbial metabolites (39,40). Likewise, endogenous microbial fermentation of nondigestible starches in gut microflora can release HDACi butyrate -believed to prevent colon cancer (31,32).…”