(N-Hydroxycarbonylbenylamino)quinolines as Selective Histone Deacetylase 6 Inhibitors Suppress Growth of Multiple Myeloma in Vitro and in Vivo
- J Med Chem. 2018 Feb 8;61(3):905-917. doi: 10.1021/acs.jmedchem.7b01404.
- 1. School of Pharmacy, College of Pharmacy, Taipei Medical University , 250 Wuxing Street, Taipei 11031, Taiwan.
- 2. National Taiwan University , Taipei 10617, Taiwan.
- 3. Center for Translational Medicine, School of Pharmacy, College of Medicine, Taipei Medical University , Taipei 11031, Taiwan.
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.