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

Abstract

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.

• Authors: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 61 Issue 3 Pg. 905-917 (02 08 2018) ISSN: 1520-4804 [Electronic] United States
• PMID: 29304284 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Histone Deacetylase Inhibitors
• Quinolines
• Histone Deacetylase 6

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Caco-2 Cells
• Cell Proliferation (drug effects)
• Histone Deacetylase 6 (antagonists & inhibitors)
• Histone Deacetylase Inhibitors (chemistry, pharmacology)
• Humans
• Multiple Myeloma (pathology)
• Quinolines (chemistry, pharmacology)
• Rats