(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

Research output: Contribution to journalArticle

  • 3 Citations

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.

LanguageEnglish
Pages905-917
Number of pages13
JournalJournal of Medicinal Chemistry
Volume61
Issue number3
DOIs
Publication statusPublished - Feb 8 2018

Fingerprint

Quinolines
Histone Deacetylase Inhibitors
Multiple Myeloma
Growth
Hydroxamic Acids
Histone Deacetylases
Heterografts
Human Activities
Bone Marrow Cells
Inhibitory Concentration 50
Permeability
Protein Isoforms
Pharmaceutical Preparations
In Vitro Techniques
Neoplasms

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

(N-Hydroxycarbonylbenylamino)quinolines as Selective Histone Deacetylase 6 Inhibitors Suppress Growth of Multiple Myeloma in Vitro and in Vivo. / Lee, Hsueh Yun; Nepali, Kunal; Huang, Fang I.; Chang, Chih Yi; Lai, Mei Jung; Li, Yu Hsuan; Huang, Hsiang Ling; Yang, Chia Ron; Liou, Jing Ping.

In: Journal of Medicinal Chemistry, Vol. 61, No. 3, 08.02.2018, p. 905-917.

Research output: Contribution to journalArticle

Lee, Hsueh Yun ; Nepali, Kunal ; Huang, Fang I. ; Chang, Chih Yi ; Lai, Mei Jung ; Li, Yu Hsuan ; Huang, Hsiang Ling ; Yang, Chia Ron ; Liou, Jing Ping. / (N-Hydroxycarbonylbenylamino)quinolines as Selective Histone Deacetylase 6 Inhibitors Suppress Growth of Multiple Myeloma in Vitro and in Vivo. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 3. pp. 905-917.
@article{4869b88dc0194d50ae28b06aaed8cb93,
title = "(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.",
author = "Lee, {Hsueh Yun} and Kunal Nepali and Huang, {Fang I.} and Chang, {Chih Yi} and Lai, {Mei Jung} and Li, {Yu Hsuan} and Huang, {Hsiang Ling} and Yang, {Chia Ron} and Liou, {Jing Ping}",
year = "2018",
month = "2",
day = "8",
doi = "10.1021/acs.jmedchem.7b01404",
language = "English",
volume = "61",
pages = "905--917",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "3",

}

TY - JOUR

T1 - (N-Hydroxycarbonylbenylamino)quinolines as Selective Histone Deacetylase 6 Inhibitors Suppress Growth of Multiple Myeloma in Vitro and in Vivo

AU - Lee, Hsueh Yun

AU - Nepali, Kunal

AU - Huang, Fang I.

AU - Chang, Chih Yi

AU - Lai, Mei Jung

AU - Li, Yu Hsuan

AU - Huang, Hsiang Ling

AU - Yang, Chia Ron

AU - Liou, Jing Ping

PY - 2018/2/8

Y1 - 2018/2/8

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85041932091&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85041932091&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.7b01404

DO - 10.1021/acs.jmedchem.7b01404

M3 - Article

VL - 61

SP - 905

EP - 917

JO - Journal of Medicinal Chemistry

T2 - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 3

ER -