Design of novel histone deacetylase inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 16, 2007, Pages 4619-4624

  Siliphaivanh, Phieng ^a   Harrington, Paul ^a   Witter, David J ^a   Otte, Karin ^a   Tempest, Paul ^a   Kattar, Sam ^a   Kral, Astrid M ^a   Fleming, Judith C ^a   Deshmukh, Sujal V ^a   Harsch, Andreas ^a   Secrist, Paul J ^a   Miller, Thomas A ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Histone deacetylases; Malonyl benzamides

Indexed keywords

2 AMINOPHENYL BENZAMIDE; HISTONE DEACETYLASE INHIBITOR; UNCLASSIFIED DRUG; VORINOSTAT;

ARTICLE; BINDING AFFINITY; CANCER CHEMOTHERAPY; CUTANEOUS T CELL LYMPHOMA; DRUG BIOAVAILABILITY; DRUG DESIGN; DRUG IDENTIFICATION; DRUG MECHANISM; NONHUMAN; STRUCTURE ACTIVITY RELATION;

ANTINEOPLASTIC AGENTS; DRUG DESIGN; HISTONE DEACETYLASES; MOLECULAR STRUCTURE; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 34447330994     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.05.080     Document Type: Article

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25. 2, viable cells were quantitated using Vialight Plus (Cambrex) according to manufacturer's instructions.
26. clog P was calculated using ACD lab software.
27. HDAC enzymatic activities were determined by the following procedure: 3× serial dilutions of a 10 mM solution of inhibitor were performed in DMSO followed by a 20× dilution into assay buffer. Twenty microliters of HDAC was preincubated with 5 μl diluted compound at RT for 10 min. The reaction was initiated by the addition of 25 μl of the appropriate substrate (HDACs 1, 2, 3, and 6: Fluor-de-Lys substrate KI-104; HDAC8: Fluor-de-Lys HDAC8 substrate KI-178), incubated 15 (HDAC8) or 60 (HDACs 1, 2, 3, and 6) minutes at 37 °C, before adding 50 μl of the appropriate development solution. The development solution for HDACs 1, 2, 3, and 6 was 167×-diluted 20× Developer Concentrate (BIOMOL: KI-105) plus 10 μM SAHA. For HDAC8, the development solution was 100×-diluted 5× Developer Concentrate (BIOMOL: KI-176) plus 10 μM SAHA. The assay was read in a VictorV plate reader (Perkin-Elmer, Wellesley, MA) at Ex 360 nm/Em 460 nm.The substrate for HDAC1, HDAC2, HDAC3, and HDAC6 was 30 μM Fluor-de-Lys substrate (BIOMOL: KI-104) and for HDAC8, 30 μM Fluor-de-Lys HDAC8 substrate (BIOMOL: KI-178). The development solution for HDAC1, HDAC2, HDAC3, and HDAC6 was 167×-diluted 20× Developer Concentrate (BIOMOL: KI-105) plus 10 μM SAHA. For HDAC8, the development solution was 100×-diluted 5× Developer Concentrate (BIOMOL: KI-176) plus 10 μM SAHA. HDAC final concentration in the reaction was 1-30 nM. HDAC8 was a generous gift of Paola Gallinari from Institute for Research in Molecular Biology, Pomezia, Italy. Carboxy-terminal FLAG-tagged human HDACs 1, 2, 3 (co-expressed with the domain of SMRT), and 6 were overexpressed in mammalian cells and affinity-purified using an anti-Flag antibody matrix, eluted from the matrix with 100 μg/ml of a competing FLAG peptide in 20 mM Tris-Cl, pH 8.0, 150 mM NaCl, 10% glycerol, and protease inhibitor cocktail (Roche cat. No. 1836153).