Potent Histone Deacetylase Inhibitors Derived from 4-(Aminomethyl)-N-hydroxybenzamide with High Selectivity for the HDAC6 Isoform

被引：38

作者：

Blackburn, Christopher ^{[1
]}

Barrett, Cynthia ^{[1
]}

Chin, Janice ^{[1
]}

Garcia, Kris ^{[1
]}

Gigstad, Kenneth ^{[1
]}

Gould, Alexandra ^{[1
]}

Gutierrez, Juan ^{[1
]}

Harrison, Sean ^{[1
]}

Hoar, Kara ^{[1
]}

Lynch, Chrissie ^{[1
]}

Rowland, R. Scott ^{[1
]}

Tsu, Chris ^{[1
]}

Ringeling, John ^{[1
]}

Xu, He ^{[1
]}

机构：

[1] Millennium Pharmaceut Inc, Discovery, Cambridge, MA 02139 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 18期

关键词：

ZINC-BINDING; PROTEASOME; CHEMISTRY; AUTOPHAGY; PATHWAY; DESIGN; CANCER; DOMAIN;

D O I：

10.1021/jm400385r

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A screen for HDAC6 inhibitors identified acyl derivatives of 4-(aminomethyl)-N-hydroxybenzamide as potent leads with unexpected selectivity over the other subtypes. We designed and synthesized constrained heterocyclic analogues such as tetrahydroisoquinolines that show further enhanced HDAC6 selectivity and inhibitory activity in cellular assays. Selectivity may be attributed to the benzylic spacer more effectively accessing the wider channel of HDAC6 compared to other HDAC subtypes as well as hydrophobic capping groups interacting with the protein surface near the rim of the active site.

引用

页码：7201 / 7211

页数：11

共 22 条

[1] Series of potent histone deacetylase inhibitors with unprecedented selectivity for the HDAC6 isoform
Xu, He
Blackburn, Christopher
Brunson, Mable
Chin, Janice
Gigstad, Kenneth
Gould, Alexandra
Gutierrez, Juan
Tsu, Chris
Ringeling, John
Barrett, Cynthia
Garcia, Kris
Harrison, Sean
Lynch, Chrissie
Hoar, Kara
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2013, 245
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Rahil, Jubrail
Lefebvre, Sylvain
Panetta, Anthony
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[3] Role of Fluorination in the Histone Deacetylase 6 (HDAC6) Selectivity of Benzohydroxamate-Based Inhibitors
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ACS MEDICINAL CHEMISTRY LETTERS, 2021, 12 (11): : 1810 - 1817
[4] Hydroxyl Ketone-Based Histone Deacetylase Inhibitors To Gain Insight into Class I HDAC Selectivity versus That of HDAC6
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[6] Merging of ruxolitinib and vorinostat leads to highly potent inhibitors of JAK2 and histone deacetylase 6 (HDAC6)
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[7] The structural requirements of histone deacetylase inhibitors: C4-modified SAHA analogs display dual HDAC6/HDAC8 selectivity
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[8] Histone deacetylase inhibitors derived from 1,2,3,4-tetrahydropyrrolo[1,2-a] pyrazine and related heterocycles selective for the HDAC6 isoform
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Barrett, Cynthia
Brunson, Mable
Chin, Janice
England, Dylan
Garcia, Kris
Gigstad, Kenneth
Gould, Alexandra
Gutierrez, Juan
Hoar, Kara
Rowland, R. Scott
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[9] Structural requirements of histone deacetylase inhibitors: Suberoylanilide hydroxamic acid analogs modified at the C4 position display HDAC6 selectivity
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ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2016, 252
[10] Novel biphenyl-based scaffold as potent and selective histone deacetylase 6 (HDAC6) inhibitors: Identification, development and pharmacological evaluation
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2022, 233

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