Phenylglycine and phenylalanine derivatives as potent and selective HDAC1 inhibitors (SHI-1).
An HTS screening campaign identified a series of low molecular weight phenols that showed excellent selectivity (>100-fold) for HDAC1/HDAC2 over other Class I and Class II HDACs. Evolution and optimization of this HTS hit series provided HDAC1-selective (SHI-1) compounds with excellent anti-proliferative activity and improved physical properties. Dose-dependent efficacy in a mouse HCT116 xenograft model was demonstrated with a phenylglycine SHI-1 analog.
Wilson
Kevin J
KJ
Department of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. kevin_wilson2@merck.com
Witter
David J
DJ
Grimm
Jonathan B
JB
Siliphaivanh
Phieng
P
Otte
Karin M
KM
Kral
Astrid M
AM
Fleming
Judith C
JC
Harsch
Andreas
A
Hamill
Julie E
JE
Cruz
Jonathan C
JC
Chenard
Melissa
M
Szewczak
Alexander A
AA
Middleton
Richard E
RE
Hughes
Bethany L
BL
Dahlberg
William K
WK
Secrist
J Paul
JP
Miller
Thomas A
TA
D000107:Acetylation; D000577:Amides; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004285:Dogs; D000072237:ERG1 Potassium Channel; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008253:Macaca mulatta; D051379:Mice; D015394:Molecular Structure; D010649:Phenylalanine / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000577:Amides; D000072237:ERG1 Potassium Channel; D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; D056572:Histone Deacetylase Inhibitors; C027797:phenylglycine chloride; D010649:Phenylalanine; C110550:HDAC1 protein, human; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1; D005998:Glycine