title: 2-Anilino-4-(thiazol-5-yl)pyrimidine CDK inhibitors: synthesis, SAR analysis, X-ray crystallography, and biological activity.
abstract: Following the identification through virtual screening of 4-(2,4-dimethyl-thiazol-5-yl)pyrimidin-2-ylamines as moderately potent inhibitors of cyclin-dependent kinase-2 (CDK2), a CDK inhibitor analogue program was initiated. The first aims were to optimize potency and to evaluate the cellular mode of action of lead candidate molecules. Here the synthetic chemistry, the structure-guided design approach, and the structure-activity relationships (SARs) that led to the discovery of 2-anilino-4-(thiazol-5-yl)pyrimidine ATP-antagonistic CDK2 inhibitors, many with very low nM K(i)s against CDK2, are reported. Furthermore, X-ray crystal structures of four representative analogues from our chemical series in complex with CDK2 are presented, and these structures are used to rationalize the observed biochemical SARs. Finally results are reported that show, using the most potent CDK2 inhibitor compound from the current series, that the observed antiproliferative and proapoptotic effects are consistent with cellular CDK2 and CDK9 inhibition.
authors.affiliation: Cyclacel Limited, James Lindsay Place, Dundee DD1 5JJ, Scotland, UK.
authors.forename: Shudong
authors.initials: S
authors.lastname: Wang
authors.forename: Christopher
authors.initials: C
authors.lastname: Meades
authors.forename: Gavin
authors.initials: G
authors.lastname: Wood
authors.forename: Andrew
authors.initials: A
authors.lastname: Osnowski
authors.forename: Sian
authors.initials: S
authors.lastname: Anderson
authors.forename: Rhoda
authors.initials: R
authors.lastname: Yuill
authors.forename: Mark
authors.initials: M
authors.lastname: Thomas
authors.forename: Mokdad
authors.initials: M
authors.lastname: Mezna
authors.forename: Wayne
authors.initials: W
authors.lastname: Jackson
authors.forename: Carol
authors.initials: C
authors.lastname: Midgley
authors.forename: Gary
authors.initials: G
authors.lastname: Griffiths
authors.forename: Ian
authors.initials: I
authors.lastname: Fleming
authors.forename: Simon
authors.initials: S
authors.lastname: Green
authors.forename: Iain
authors.initials: I
authors.lastname: McNae
authors.forename: Su-Ying
authors.initials: SY
authors.lastname: Wu
authors.forename: Campbell
authors.initials: C
authors.lastname: McInnes
authors.forename: Daniella
authors.initials: D
authors.lastname: Zheleva
authors.forename: Malcolm D
authors.initials: MD
authors.lastname: Walkinshaw
authors.forename: Peter M
authors.initials: PM
authors.lastname: Fischer
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors*; D006801:Humans; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D011743:Pyrimidines; D013844:Thiazoles; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D042863:Cyclin-Dependent Kinase 9