title: 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).
abstract: 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.
authors.affiliation: MethylGene Inc., Department of Medicinal Chemistry, 7220 Frederick-Banting, Montréal, Que., Canada H4S 2A1. raeppels@methylgene.com
authors.forename: Stéphane
authors.initials: S
authors.lastname: Raeppel
authors.forename: Nancy
authors.initials: N
authors.lastname: Zhou
authors.forename: Frédéric
authors.initials: F
authors.lastname: Gaudette
authors.forename: Silvana
authors.initials: S
authors.lastname: Leit
authors.forename: Isabelle
authors.initials: I
authors.lastname: Paquin
authors.forename: Guillaume
authors.initials: G
authors.lastname: Larouche
authors.forename: Oscar
authors.initials: O
authors.lastname: Moradei
authors.forename: Sylvie
authors.initials: S
authors.lastname: Fréchette
authors.forename: Ljubomir
authors.initials: L
authors.lastname: Isakovic
authors.forename: Daniel
authors.initials: D
authors.lastname: Delorme
authors.forename: Marielle
authors.initials: M
authors.lastname: Fournel
authors.forename: Ann
authors.initials: A
authors.lastname: Kalita
authors.forename: Aihua
authors.initials: A
authors.lastname: Lu
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Trachy-Bourget
authors.forename: Pu Theresa
authors.initials: PT
authors.lastname: Yan
authors.forename: Jianhong
authors.initials: J
authors.lastname: Liu
authors.forename: Jubrail
authors.initials: J
authors.lastname: Rahil
authors.forename: James
authors.initials: J
authors.lastname: Wang
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Besterman
authors.forename: Koji
authors.initials: K
authors.lastname: Murakami
authors.forename: Zuomei
authors.initials: Z
authors.lastname: Li
authors.forename: Arkadii
authors.initials: A
authors.lastname: Vaisburg
mesh_terms: 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
chemical_list: 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