(N-Hydroxycarbonylbenylamino)quinolines as Selective Histone Deacetylase 6 Inhibitors Suppress Growth of Multiple Myeloma in Vitro and in Vivo

Hsueh Yun Lee, Kunal Nepali, Fang I. Huang, Chih Yi Chang, Mei Jung Lai, Yu Hsuan Li, Hsiang Ling Huang, Chia Ron Yang, Jing Ping Liou

研究成果: 雜誌貢獻文章

20 引文 斯高帕斯(Scopus)

摘要

A series of bicyclic arylamino/heteroarylamino hydroxamic acids (7-31) have been examined as novel histone deacetylase 6 (HDAC6) inhibitors. One compound (13) exhibits remarkable inhibitory activity of HDAC6 with an IC50 value of 0.29 nM, which is 4,000-43,000 times more selective over other HDAC isoforms. Compound 13 was shown to have antiproliferative activity against human multiple myeloma RPMI 8226, U266, and NCI-H929 cells with no effect on normal bone marrow cells. Compound 13, as a single drug, suppresses the growth of tumors by a %TGI factor of 60.4% in human multiple myeloma RPMI 8226 xenograft models and, in combination with bortezomib, shows significant in vivo antitumor activity (%TGI = 86.2%). Compound 13 also demonstrates good human hepatocytic stability and high permeability, without any effect on mutagenicity and cytotoxicity. Thus, compound 13 is a potent HDAC6 inhibitor that could be developed for the treatment of multiple myeloma in the future.
原文英語
頁(從 - 到)905-917
頁數13
期刊Journal of Medicinal Chemistry
61
發行號3
DOIs
出版狀態已發佈 - 二月 8 2018

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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