A series of novel, potent, and selective histone deacetylase inhibitors

被引：67

作者：

Jones, Philip

Altamura, Sergio

Chakravarty, Prasun K.

Cecchetti, Ottavia

De Francesco, Raffaele

Gallinari, Paola

Ingenito, Raffaele

Meinke, Peter T.

Petrocchi, Alessia

Rowley, Michael

Scarpelli, Rita

Serafini, Sergio

Steinkuhler, Christian

机构：

[1] IRBM, Merck Res Labs, I-00040 Pomezia, Italy

[2] Merck Res Labs, Rahway, NJ 07065 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 23期

关键词：

histone deacetylase inhibitor; HDAC; SAR studies;

D O I：

10.1016/j.bmcl.2006.09.002

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Histone deacetylase (HDAC) inhibitors offer a promising strategy for cancer therapy and the first generation HDAC inhibitors are currently in clinical trials. A structurally novel series of HDAC inhibitors based on the natural cyclic tetrapeptide Apicidin is described. Selected screening of the sample collection looking for L-2-amino-8-oxodecanoic acid (L-Aoda) derivatives identified a small acyclic lead molecule 1 with the unusual ketone zinc binding group. SAR studies around this lead resulted in optimization to potent, low molecular weight, selective, non-hydroxamic acid HDAC inhibitors, equipotent to current clinical candidates. (c) 2006 Elsevier Ltd. All rights reserved.

引用

收藏

页码：5948 / 5952

页数：5

相关论文

共 18 条

[1] Short-Chain Fatty Acid Inhibitors of Histone Deacetylases: Promising Anticancer Therapeutics? [J].

Chen, James S. ;

Faller, Douglas V. ;

Spanjaard, Remco A. .

CURRENT CANCER DRUG TARGETS, 2003, 3 (03) :219-236

[2] Acetylation and chromosomal functions [J].

Cheung, WL ;

Briggs, SD ;

Allis, CD .

CURRENT OPINION IN CELL BIOLOGY, 2000, 12 (03) :326-333

[3]

Colletti SL, 2001, BIOORG MED CHEM LETT, V11, P107, DOI 10.1016/S0960-894X(00)00604-1

[4] Apicidin: A novel antiprotozoal agent that inhibits parasite histone deacetylase [J].

DarkinRattray, SJ ;

Gurnett, AM ;

Myers, RW ;

Dulski, PM ;

Crumley, TM ;

Allocco, JJ ;

Cannova, C ;

Meinke, PT ;

Colletti, SL ;

Bednarek, MA ;

Singh, SB ;

Goetz, MA ;

Dombrowski, AW ;

Polishook, JD ;

Schmatz, DM .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (23) :13143-13147

[5] Histone deacetylases (HDACs): characterization of the classical HDAC family [J].

De Ruijter, AJM ;

Van Gennip, AH ;

Caron, HN ;

Kemp, S ;

Van Kuilenburg, ABP .

BIOCHEMICAL JOURNAL, 2003, 370 :737-749

[6] Trifluoromethyl ketones as inhibitors of histone deacetylase [J].

Frey, RR ;

Wada, CK ;

Garland, RB ;

Curtin, ML ;

Michaelides, MR ;

Li, JL ;

Pease, LJ ;

Glaser, KB ;

Marcotte, PA ;

Bouska, JJ ;

Murphy, SS ;

Davidsen, SK .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2002, 12 (23) :3443-3447

[7] ISOLATION AND STRUCTURAL ELUCIDATION OF NEW CYCLOTETRAPEPTIDES, TRAPOXIN-A AND TRAPOXIN-B, HAVING DETRANSFORMATION ACTIVITIES AS ANTITUMOR AGENTS [J].

ITAZAKI, H ;

NAGASHIMA, K ;

SUGITA, K ;

YOSHIDA, H ;

KAWAMURA, Y ;

YASUDA, Y ;

MATSUMOTO, K ;

ISHII, K ;

UOTANI, N ;

NAKAI, H ;

TERUI, A ;

YOSHIMATSU, S ;

IKENISHI, Y ;

NAKAGAWA, Y .

JOURNAL OF ANTIBIOTICS, 1990, 43 (12) :1524-1532

[8] Histone-deacetylase inhibitors: Novel drugs for the treatment of cancer [J].

Johnstone, RW .

NATURE REVIEWS DRUG DISCOVERY, 2002, 1 (04) :287-299

[9] Histone deacetylases and cancer: Causes and therapies [J].

Marks, PA ;

Rifkind, RA ;

Richon, VM ;

Breslow, R ;

Miller, T ;

Kelly, WK .

NATURE REVIEWS CANCER, 2001, 1 (03) :194-202

[10] Histone deacetylase inhibitors [J].

Miller, TA ;

Witter, DJ ;

Belvedere, S .

JOURNAL OF MEDICINAL CHEMISTRY, 2003, 46 (24) :5097-5116