title: Discovery of N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amine aurora kinase inhibitors.
abstract: Through cell-based screening of our kinase-directed compound collection, we discovered that a subset of N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amines were potent cytotoxic agents against cancer cell lines, suppressed mitotic histone H3 phosphorylation, and caused aberrant mitotic phenotypes. It was subsequently established that these compounds were in fact potent inhibitors of aurora A and B kinases. It was shown that potency and selectivity of aurora kinase inhibition correlated with the presence of a substituent at the aniline para-position in these compounds. The anticancer effects of lead compound 4-methyl-5-(2-(4-morpholinophenylamino)pyrimidin-4-yl)thiazol-2-amine (18; K(i) values of 8.0 and 9.2 nM for aurora A and B, respectively) were shown to emanate from cell death following mitotic failure and increased polyploidy as a consequence of cellular inhibition of aurora A and B kinases. Preliminary in vivo assessment showed that compound 18 was orally bioavailable and possessed anticancer activity. Compound 18 (CYC116) is currently undergoing phase I clinical evaluation in cancer patients.
authors.affiliation: Cyclacel Ltd., 1 James Lindsay Place, Dundee DD1 5JJ, Scotland, UK.
authors.forename: Shudong
authors.initials: S
authors.lastname: Wang
authors.forename: Carol A
authors.initials: CA
authors.lastname: Midgley
authors.forename: Frederic
authors.initials: F
authors.lastname: Scaërou
authors.forename: Joanna B
authors.initials: JB
authors.lastname: Grabarek
authors.forename: Gary
authors.initials: G
authors.lastname: Griffiths
authors.forename: Wayne
authors.initials: W
authors.lastname: Jackson
authors.forename: George
authors.initials: G
authors.lastname: Kontopidis
authors.forename: Steven J
authors.initials: SJ
authors.lastname: McClue
authors.forename: Campbell
authors.initials: C
authors.lastname: McInnes
authors.forename: Christopher
authors.initials: C
authors.lastname: Meades
authors.forename: Mokdad
authors.initials: M
authors.lastname: Mezna
authors.forename: Andy
authors.initials: A
authors.lastname: Plater
authors.forename: Iain
authors.initials: I
authors.lastname: Stuart
authors.forename: Mark P
authors.initials: MP
authors.lastname: Thomas
authors.forename: Gavin
authors.initials: G
authors.lastname: Wood
authors.forename: Rosemary G
authors.initials: RG
authors.lastname: Clarke
authors.forename: David G
authors.initials: DG
authors.lastname: Blake
authors.forename: Daniella I
authors.initials: DI
authors.lastname: Zheleva
authors.forename: David P
authors.initials: DP
authors.lastname: Lane
authors.forename: Robert C
authors.initials: RC
authors.lastname: Jackson
authors.forename: David M
authors.initials: DM
authors.lastname: Glover
authors.forename: Peter M
authors.initials: PM
authors.lastname: Fischer
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D008958:Models, Molecular; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D013379:Substrate Specificity; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C550465:4-methyl-5-(2-(4-morpholinophenylamino)pyrimidin-4-yl)thiazol-2-amine; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000255:Adenosine Triphosphate; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases