title: Discovery of Selective Histone Deacetylase 6 Inhibitors Using the Quinazoline as the Cap for the Treatment of Cancer.
abstract: Novel selective histone deacetylase 6 (HDAC6) inhibitors using the quinazoline as the cap were designed, synthesized, and evaluated for HDAC enzymatic assays. N-Hydroxy-4-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)butanamide, 23bb, was the most potent selective inhibitor for HDAC6 with an IC50 of 17 nM and showed 25-fold and 200-fold selectivity relative to HDAC1 and HDAC8, respectively. In vitro, 23bb presented low nanomolar antiproliferative effects against panel of cancer cell lines. Western blot analysis further confirmed that 23bb increased acetylation level of α-tubulin in vitro. 23bb has a good pharmacokinetic profile with oral bioavailability of 47.0% in rats. In in vivo efficacy evaluations of colorectal HCT116, acute myelocytic leukemia MV4-11, and B cell lymphoma Romas xenografts, 23bb more effectively inhibited the tumor growth than SAHA even at a 4-fold reduced dose or ACY-1215 at the same dose. Our results indicated that 23bb is a potent oral anticancer candidate for selective HDAC6 inhibitor and deserves further investigation.
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, College of Chemistry, Sichuan University, Chengdu, 610064, China.|State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
authors.forename: Taijin
authors.initials: T
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Hematology and Research Laboratory of Hematology, West China Hospital of Sichuan University , Chengdu, 610041, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Niu
authors.affiliation: Guangdong Zhongsheng Pharmaceutical Co., Ltd., Dongguan, Guangdong 523325, China.
authors.forename: Zhuowei
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Guangdong Zhongsheng Pharmaceutical Co., Ltd., Dongguan, Guangdong 523325, China.
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Guangdong Zhongsheng Pharmaceutical Co., Ltd., Dongguan, Guangdong 523325, China.
authors.forename: Chaofeng
authors.initials: C
authors.lastname: Long
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
authors.forename: Minghai
authors.initials: M
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiang
authors.affiliation: Department of Hematology and Research Laboratory of Hematology, West China Hospital of Sichuan University , Chengdu, 610041, China.
authors.forename: Yuyao
authors.initials: Y
authors.lastname: Yi
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, College of Chemistry, Sichuan University, Chengdu, 610064, China.
authors.forename: Jingsong
authors.initials: J
authors.lastname: You
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, College of Chemistry, Sichuan University, Chengdu, 610064, China.|State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Chen
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005260:Female; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011799:Quinazolines / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D014404:Tubulin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D011799:Quinazolines; D014404:Tubulin; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases