Transforming growth factor beta mimetics: discovery of 7-[4-(4-cyanophenyl)phenoxy]-heptanohydroxamic acid, a biaryl hydroxamate inhibitor of histone deacetylase.
Transforming growth factor beta (TGF-beta) is a multifunctional protein that has been shown to possess potent growth-inhibitory activity. To identify small molecular weight compounds with TGF-beta-like activities, high throughput screening was performed using mink lung epithelial cells stably transfected with a TGF-beta-responsive plasminogen activator inhibitor 1 promoter/luciferase construct. Biaryl hydroxamate compounds were identified that demonstrated TGF-beta-like activities. 7-[4-(4-cyanophenyl)phenoxy]-heptanohydroxamic acid (A-161906) demonstrated complete TGF-beta-like agonist activity in the plasminogen activator inhibitor 1/luciferase construct. A-161906 inhibited the proliferation of multiple cell lines in a concentration-dependent manner. Cells were growth arrested at the G1-S checkpoint similar to TGF-beta. Consistent with the G1-S arrest, A-161906 induced the expression of the cyclin-dependent kinase inhibitor p21waf1/cip1. A-161906 produced many cellular effects similar to that of TGF-beta but did not displace labeled TGF-beta from its receptors. Cells with mutations in either of the TGF-beta receptors I or II were growth-arrested by A-161906. Therefore, the site of action of A-161906 appears to be distal to the receptors and possibly involved with the signaling events controlled by TGF-beta. The TGF-beta mimetic effect of A-161906 can be partially, if not entirely, explained by its activity as a histone deacetylase (HDAC) inhibitor. A-161906 demonstrated potent HDAC-inhibitory activity (IC50 = 9 nM). A-161906 is a novel small molecular weight compound (< 400 MW) having TGF-beta mimetic activity as a result of its potent HDAC-inhibitory activity. These results and those of others demonstrate the importance of HDACs in regulation of the TGF-beta signaling pathway(s).
Glaser
Keith B
KB
Global Pharmaceutical Research & Development, Abbott Laboratories, Abbott Park, Illinois 60064-6121, USA. keith.glaser@abbott.com
Li
Junling
J
Aakre
Mary E
ME
Morgan
Douglas W
DW
Sheppard
George
G
Stewart
Kent D
KD
Pollock
Jennifer
J
Lee
Paul
P
O'Connor
Chad Z
CZ
Anderson
Steven N
SN
Mussatto
Donna J
DJ
Wegner
Craig W
CW
Moses
Harold L
HL
D000107:Acetylation; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle; D002455:Cell Division; D002460:Cell Line; D017364:Collagenases / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005353:Fibronectins / Q000096:biosynthesis; D016193:G1 Phase; D018260:Gelsolin / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D015603:Keratinocytes / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008168:Lung / Q000166:cytology; D051379:Mice; D008907:Mink; D008956:Models, Chemical; D010641:Phenotype; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D011401:Promoter Regions, Genetic; D016196:S Phase; D013997:Time Factors; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000737:chemistry / Q000494:pharmacology*
C472783:7-(4-(4-cyanophenyl)phenoxy)heptanohydroxamic acid; D001713:Biphenyl Compounds; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D005353:Fibronectins; D018260:Gelsolin; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D017395:Plasminogen Activator Inhibitor 1; D016212:Transforming Growth Factor beta; D008156:Luciferases; D017364:Collagenases