title: Synthesis, structure-activity relationship and biological evaluation of 2,4,5-trisubstituted pyrimidine CDK inhibitors as potential anti-tumour agents.
abstract: A series of 2,4,5-trisubstituted pyrimidines have been synthesised and characterised, which exhibited potent CDK inhibition and anti-proliferative activities. The structure-activity relationship is analysed and a rational for CDK9 selectivity is discussed. Compound 9s, possessing appreciable selectivity for CDK9 over other CDKs, is capable of activating caspase 3, reducing the level of Mcl-1 anti-apoptotic protein, and inducing cancer cell apoptosis.
authors.affiliation: School of Pharmacy and Centre for Biomolecular Sciences, University of Nottingham, Nottingham NG7 2RD, UK.
authors.forename: Hao
authors.initials: H
authors.lastname: Shao
authors.forename: Shenhua
authors.initials: S
authors.lastname: Shi
authors.forename: David W
authors.initials: DW
authors.lastname: Foley
authors.forename: Frankie
authors.initials: F
authors.lastname: Lam
authors.forename: Abdullah Y
authors.initials: AY
authors.lastname: Abbas
authors.forename: Xiangrui
authors.initials: X
authors.lastname: Liu
authors.forename: Shiliang
authors.initials: S
authors.lastname: Huang
authors.forename: Xiangrui
authors.initials: X
authors.lastname: Jiang
authors.forename: Nadiah
authors.initials: N
authors.lastname: Baharin
authors.forename: Peter M
authors.initials: PM
authors.lastname: Fischer
authors.forename: Shudong
authors.initials: S
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D018844:Cyclin-Dependent Kinases; C030986:pyrimidine
keywords: Anti-cancer drug discovery; CDK9 inhibitors; Inhibitor design; Mcl-1 anti-apoptotic proteins; RNA polymerase II