title: Discovery of novel Thieno[2,3-d]pyrimidin-4-yl hydrazone-based cyclin-dependent kinase 4 inhibitors: synthesis, biological evaluation and structure-activity relationships.
abstract: The design, synthesis, and evaluation of novel thieno[2,3-d]pyrimidin-4-yl hydrazone analogues as cyclin-dependent kinase 4 (CDK4) inhibitors are described. In continuing our program aim to search for potent CDK4 inhibitors, the introduction of a thiazole group at the hydrazone part has led to marked enhancement of chemical stability. Furthermore, by focusing on the optimization at the C-4' position of the thiazole ring and the C-6 position of the thieno[2,3-d]pyrimidine moiety, compound 35 has been identified with efficacy in a xenograft model of HCT116 cells. In this paper, the potency, selectivity profile, and structure-activity relationships of our synthetic compounds are discussed.
authors.affiliation: Lead Discovery & Optimization Research Laboratories II, Daiichi Sankyo Co., Ltd., Japan. horiuchi.takao.pi@daiichisankyo.co.jp
authors.forename: Takao
authors.initials: T
authors.lastname: Horiuchi
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Takeda
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Haginoya
authors.forename: Masaki
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Motoko
authors.initials: M
authors.lastname: Nagata
authors.forename: Mayumi
authors.initials: M
authors.lastname: Kitagawa
authors.forename: Kouichi
authors.initials: K
authors.lastname: Akahane
authors.forename: Kouichi
authors.initials: K
authors.lastname: Uoto
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D006835:Hydrazones; D011743:Pyrimidines; D013844:Thiazoles; D051358:Cyclin-Dependent Kinase 4