title: Application of p21 and klf2 reporter gene assays to identify selective histone deacetylase inhibitors for cancer therapy.
abstract: Novel 2-aminoanilide histone deacetylase (HDAC) inhibitors were designed to increase their contact with surface residues surrounding the HDAC active site compared to the contacts made by existing clinical 2-aminoanilides such as SNDX-275, MGCD0103, and Chidamide. Their HDAC selectivity was assessed using p21 and klf2 reporter gene assays in HeLa and A204 cells, respectively, which provide a cell-based readout for the inhibition of HDACs associated either with the p21 or klf2 promoter. A subset of the designed compounds selectively induced p21 over klf2 relative to the clinical reference compound SNDX-275. A representative lead compound from this subset had antiproliferative effects in cancer cells associated with induction of acetylated histone H4, endogenous p21, cell cycle arrest, and apoptosis. The p21- versus klf2-selective compounds described herein may provide a chemical starting point for developing clinically-differentiated HDAC inhibitors for cancer therapy.
authors.affiliation: Roche R&D Center China Ltd, 720 Cai Lun Road, Building 5, Pudong, Shanghai 201203, PR China. jason.wong@roche.com
authors.forename: Jason C
authors.initials: JC
authors.lastname: Wong
authors.forename: Lei
authors.initials: L
authors.lastname: Guo
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Peng
authors.forename: Weixing
authors.initials: W
authors.lastname: Zhang
authors.forename: Nan
authors.initials: N
authors.lastname: Zhang
authors.forename: Wayne
authors.initials: W
authors.lastname: Lai
authors.forename: Zhenshan
authors.initials: Z
authors.lastname: Zhang
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Zhang
authors.forename: Shan
authors.initials: S
authors.lastname: Song
authors.forename: Desi
authors.initials: D
authors.lastname: Pan
authors.forename: Chuanming
authors.initials: C
authors.lastname: Xie
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Ning
authors.forename: Xianping
authors.initials: X
authors.lastname: Lu
authors.forename: Yun
authors.initials: Y
authors.lastname: He
authors.forename: Li
authors.initials: L
authors.lastname: Chen
mesh_terms: D000631:Aminopyridines / Q000627:therapeutic use; D000813:Anilides / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D001549:Benzamides / Q000627:therapeutic use; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D017930:Genes, Reporter; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D009369:Neoplasms / Q000188:drug therapy; D011401:Promoter Regions, Genetic; D011743:Pyrimidines / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D000631:Aminopyridines; D000813:Anilides; D000970:Antineoplastic Agents; D001549:Benzamides; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D011743:Pyrimidines; C547816:N-(2-amino-5-fluorobenzyl)-4-(N-(pyridine-3-acrylyl)aminomethyl)benzamide; C523184:mocetinostat; D006655:Histone Deacetylases