SAR and biological evaluation of analogues of a small molecule histone deacetylase inhibitor N-(2-aminophenyl)-4-((4-(pyridin-3-yl)pyrimidin-2-ylamino)methyl)benzamide (MGCD0103).
Analogues of the clinical compound MGCD0103 (A) were designed and synthesized. These compounds inhibit recombinant human HDAC1 with IC(50) values in the sub-micromolar range. In human cancer cells growing in culture these compounds induce hyperacetylation of histones, cause expression of the tumor suppressor protein p21(WAF1/CIP1), and inhibit cellular proliferation. Lead molecule of the series, compound 25 is metabolically stable, possesses favorable pharmacokinetic characteristics and is orally active in vivo in different mouse tumor xenograft models.
Raeppel
Stéphane
S
MethylGene Inc., Department of Medicinal Chemistry, 7220 Frederick-Banting, Montréal, Que., Canada H4S 2A1. raeppels@methylgene.com
Zhou
Nancy
N
Gaudette
Frédéric
F
Leit
Silvana
S
Paquin
Isabelle
I
Larouche
Guillaume
G
Moradei
Oscar
O
Fréchette
Sylvie
S
Isakovic
Ljubomir
L
Delorme
Daniel
D
Fournel
Marielle
M
Kalita
Ann
A
Lu
Aihua
A
Trachy-Bourget
Marie-Claude
MC
Yan
Pu Theresa
PT
Liu
Jianhong
J
Rahil
Jubrail
J
Wang
James
J
Besterman
Jeffrey M
JM
Murakami
Koji
K
Li
Zuomei
Z
Vaisburg
Arkadii
A
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002626:Chemistry, Pharmaceutical / Q000379:methods; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D009368:Neoplasm Transplantation; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D001549:Benzamides; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D011743:Pyrimidines; C523184:mocetinostat