Reference Detail

Ref Type

Journal Article

PMID

(18292931)

Authors

Shindoh N, Mori M, Terada Y, Oda K, Amino N, Kita A, Taniguchi M, Sohda KY, Nagai K, Sowa Y, Masuoka Y, Orita M, Sasamata M, Matsushime H, Furuichi K, Sakai T

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
International journal of oncology	32	3	2008 Mar	545-55	Int J Oncol

URL

Abstract Text

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 IC50 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 p21WAF1/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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
OBP-801	OBP-801	0	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
OBP-801		YM753\|YM-753	HDAC Inhibitor 45	OBP-801 (YM753) is a histone deacetylase inhibitor belonging to the cyclic peptide class, which may induce both cell cycle arrest and apoptosis (PMID: 18292931, PMID: 23900601, PMID: 32277670).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References