NDLI: Preclinical Studies of YK-4-272, an Inhibitor of Class II Histone Deacetylases by Disruption of Nucleocytoplasmic Shuttling

Content Provider	Springer Nature Link
Author	Kong, Hye Sik Tian, Shuo Kong, Yali Du, Guanhua Zhang, Li Jung, Mira Dritschilo, Anatoly Brown, Milton L.
Copyright Year	2012
Abstract	The HDAC shuttling inhibitor, YK-4-272 functions by restricting nuclear shuttling of Class II HDACs. Pre-clinical investigations of YK-4-272 bioavailability, pharmacokinetics, in vivo toxicity and tumor growth inhibition were performed to determine its potential as an HDAC shuttling disruptor for use in clinical applications.The solubility, lipophilicity, in vitro metabolic stability, in vitro intestinal permeability, and in vivo pharmacokinetics of YK-4-272 were determined by HPLC methods. The anti-tumor activity of YK-4-272 was determined by monitoring athymic Balb/c nude mice bearing PC-3 xenografts.Oral bioavailability of YK-4-272 is supported by its solubility (0.537 mg/mL) and apparent partition coefficient of 2.0. The compound was chemically and metabolically stable and not a substrate for CYP450. In Caco-2 cell transport studies, YK-4-272 was highly permeable. The time-concentration profile of YK-4-272 in plasma resulted in a C $_{ max }$ of 2.47 μg/mL at 0.25 h with a AUC of 3.304 μg × h/mL. Treatment of PC-3 tumor xenografts with YK-4-272 showed significant growth delay.YK-4-272 is stable and bio-available following oral administration. Growth inhibition of cancer cells and tumors was observed. These studies support advancing YK-4-272 for further evaluation as a novel HDAC shuttling inhibitor for use in cancer treatment.
Starting Page	3373
Ending Page	3383
Page Count	11
File Format	PDF
ISSN	07248741
Journal	Pharmaceutical Research
Volume Number	29
Issue Number	12
e-ISSN	1573904X
Language	English
Publisher	Springer US
Publisher Date	2012-07-27
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Medical Law Biochemistry Pharmacology/Toxicology Pharmacy Biomedical Engineering
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Pharmacology Molecular Medicine Pharmacology (medical) Biotechnology Pharmaceutical Science

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