(N-Hydroxycarbonylbenylamino)quinolines as Selective Histone Deacetylase 6 Inhibitors Suppress Growth of Multiple Myeloma in Vitro and in Vivo
Journal
Journal of Medicinal Chemistry
Journal Volume
61
Journal Issue
3
Pages
905-917
Date Issued
2018
Author(s)
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 IC 50 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. ? 2018 American Chemical Society.
SDGs
Other Subjects
(n hydroxycarbonylbenylamino)quinoline derivative; 4 [(1h indazol 7 ylamino)methyl] n hydroxybenzamide; antineoplastic agent; bortezomib; histone deacetylase; histone deacetylase 6; histone deacetylase inhibitor; mesylic acid derivative; n hydroxy 3 [(quinolin 8 ylamino)methyl]benzamide; n hydroxy 3 [4 [(quinolin 5 ylamino)methyl]phenyl]acrylamide; n hydroxy 3 [4 [(quinolin 8 ylamino)methyl]phenyl]acrylamide; n hydroxy 4 (quinolin 8 ylamino)benzamide; n hydroxy 4 (quinolin 8 ylmethylamino)benzamide; n hydroxy 4 [(isoquinolin 4 ylamino)methyl]benzamide; n hydroxy 4 [(isoquinolin 5ylamino)methyl]benzamide; n hydroxy 4 [(isoquinolin 8 ylamino)methyl]benzamide; n hydroxy 4 [(quinolin 2 ylamino)methyl]benzamide; n hydroxy 4 [(quinolin 3 ylamino)methyl]benzamide; n hydroxy 4 [(quinolin 4 ylamino)methyl]benzamide; n hydroxy 4 [(quinolin 5 ylamino)methyl]benzamide; n hydroxy 4 [(quinolin 6 ylamino)methyl]benzamide; n hydroxy 4 [(quinolin 7 ylamino)methyl]benzamide; n hydroxy 4 [(quinolin 8 ylamino)methyl]benzamide; n hydroxy 4 [(quinolin 8 yloxy)methyl]benzamide; n hydroxy 4 [(quinolin 8 ylthio)methyl]benzamide; n hydroxy 4 [2 (quinolin 8 yl)ethyl]benzamide; n hydroxy 4 [[(2 methylquinolin 8 yl)amino]methyl]benzamide; n1 hydroxy n4 (quinolin 5 yl)terephthalamide; n1 hydroxy n4 (quinolin 8 ylamino)terephthalamide; unclassified drug; unindexed drug; antineoplastic agent; histone deacetylase 6; histone deacetylase inhibitor; quinoline derivative; animal experiment; animal model; antineoplastic activity; antiproliferative activity; Article; bone marrow cell; Caco-2 cell line; cancer inhibition; concentration response; controlled study; drug cytotoxicity; drug effect; drug penetration; drug potency; drug safety; drug screening; drug selectivity; drug stability; drug structure; drug targeting; drug tolerability; enzyme activity; enzyme inhibition; half life time; human; human cell; IC50; in vitro study; in vivo study; male; mouse; multiple myeloma; mutagenicity; NCI-H929 cell line; nonhuman; rat; RPMI-8226 cell line; tumor xenograft; animal; antagonists and inhibitors; cell proliferation; chemistry; multiple myeloma; pathology; Animals; Antineoplastic Agents; Caco-2 Cells; Cell Proliferation; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Humans; Multiple Myeloma; Quinolines; Rats
Type
journal article