Amino acid derivatives as histone deacetylase inhibitors.
Ongoing clinical studies indicate that inhibitors of Class I and Class II histone deacetylase (HDAC) enzymes show great promise for the treatment of cancer. Zolinza (SAHA, Zolinza) was recently approved by the FDA for the treatment of the cutaneous manifestations of cutaneous T-cell lymphoma. As a part of an ongoing effort to identify novel small molecules to target these important enzymes, we have prepared several classes of amino acid-derived HDAC1 inhibitors. The design rationale and in vitro activity against the HDAC1 enzyme and HCT116 cell line are described in this letter.
Department of Drug Design and Optimization-Medicinal Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. jed_hubbs@merck.com
Jed L
JL
Hubbs
Hua
H
Zhou
Astrid M
AM
Kral
Judith C
JC
Fleming
William K
WK
Dahlberg
Bethany L
BL
Hughes
Richard E
RE
Middleton
Alexander A
AA
Szewczak
J Paul
JP
Secrist
Thomas A
TA
Miller
D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000596:Amino Acids; D056572:Histone Deacetylase Inhibitors; D010879:Piperazines; D013876:Thiophenes; C088015:benzothiophene; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1