title: AZD5438, a potent oral inhibitor of cyclin-dependent kinases 1, 2, and 9, leads to pharmacodynamic changes and potent antitumor effects in human tumor xenografts.
abstract: Deregulation of the cell cycle has long been recognized as an essential driver of tumorigenesis, and agents that selectively target key cell cycle components continue to hold promise as potential therapeutics. We have developed AZD5438, a 4-(1-isopropyl-2-methylimidazol-5-yl)-2-(4-methylsulphonylanilino) pyrimidine, as a potent inhibitor of cyclin-dependent kinase (cdk) 1, 2, and 9 (IC(50), 16, 6, and 20 nmol/L, respectively). In vitro, AZD5438 showed significant antiproliferative activity in human tumor cell lines (IC(50) range, 0.2-1.7 micromol/L), causing inhibition of the phosphorylation of cdk substrates pRb, nucleolin, protein phosphatase 1a, and RNA polymerase II COOH-terminal domain and blocking cell cycling at G(2)-M, S, and G(1) phases. In vivo, when orally administered at either 50 mg/kg twice daily or 75 mg/kg once daily, AZD5438 inhibited human tumor xenograft growth (maximum percentage tumor growth inhibition, range, 38-153; P < 0.05). In vivo, AZD5438 reduced the proportion of actively cycling cells. Further pharmacodynamic analysis of AZD5438-treated SW620 xenografts showed that efficacious doses of AZD5438 (>40% tumor growth inhibition) maintained suppression of biomarkers, such as phospho-pRbSer(249)/Thr(252), for up to 16 hours following a single oral dose. A comparison of different schedules indicated that chronic daily oral dosing provided optimal cover to ensure antitumor efficacy. These data indicate that broad cdk inhibition may provide an effective method to impair the dysregulated cell cycle that drives tumorigenesis and AZD5438 has the pharmacologic profile that provides an ideal probe to test this premise.
authors.affiliation: AstraZeneca R&D Boston, Waltham, MA 02451, USA. Kate.Byth@AstraZeneca.com
authors.forename: Kate F
authors.initials: KF
authors.lastname: Byth
authors.forename: Andrew
authors.initials: A
authors.lastname: Thomas
authors.forename: Gareth
authors.initials: G
authors.lastname: Hughes
authors.forename: Cheryl
authors.initials: C
authors.lastname: Forder
authors.forename: Alexandra
authors.initials: A
authors.lastname: McGregor
authors.forename: Catherine
authors.initials: C
authors.lastname: Geh
authors.forename: Sandra
authors.initials: S
authors.lastname: Oakes
authors.forename: Clive
authors.initials: C
authors.lastname: Green
authors.forename: Mike
authors.initials: M
authors.lastname: Walker
authors.forename: Nicholas
authors.initials: N
authors.lastname: Newcombe
authors.forename: Stephen
authors.initials: S
authors.lastname: Green
authors.forename: Jim
authors.initials: J
authors.lastname: Growcott
authors.forename: Andy
authors.initials: A
authors.lastname: Barker
authors.forename: Robert W
authors.initials: RW
authors.lastname: Wilkinson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011923:Rats, Nude; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D011743:Pyrimidines; C521840:AZD5438; D016203:CDC2 Protein Kinase; D051357:Cyclin-Dependent Kinase 2; D042863:Cyclin-Dependent Kinase 9; D018844:Cyclin-Dependent Kinases