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.
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
Lee, H. Y., Nepali, K., Huang, F. I., Chang, C. Y., Lai, M. J., Li, Y. H., Huang, H. L., Yang, C. R., & Liou, J. P. (2018). (N-Hydroxycarbonylbenylamino)quinolines as Selective Histone Deacetylase 6 Inhibitors Suppress Growth of Multiple Myeloma in Vitro and in Vivo. Journal of Medicinal Chemistry, 61(3), 905-917. https://doi.org/10.1021/acs.jmedchem.7b01404