title: Substituted aminopyrimidine protein kinase B (PknB) inhibitors show activity against Mycobacterium tuberculosis.
abstract: A high-throughput screen against PknB, an essential serine-threonine protein kinase present in Mycobacterium tuberculosis (M. tuberculosis), allowed the identification of an aminoquinazoline inhibitor which was used as a starting point for SAR investigations. Although a significant improvement in enzyme affinity was achieved, the aminoquinazolines showed little or no cellular activity against M. tuberculosis. However, switching to an aminopyrimidine core scaffold and the introduction of a basic amine side chain afforded compounds with nanomolar enzyme binding affinity and micromolar minimum inhibitory concentrations against M. tuberculosis. Replacement of the pyrazole head group with pyridine then allowed equipotent compounds with improved selectivity against a human kinase panel to be obtained.
authors.affiliation: Centre for Therapeutics Discovery, MRC Technology, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, UK. tim.chapman@tech.mrc.ac.uk
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Chapman
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bouloc
authors.forename: Roger S
authors.initials: RS
authors.lastname: Buxton
authors.forename: Jasveen
authors.initials: J
authors.lastname: Chugh
authors.forename: Kathryn E A
authors.initials: KE
authors.lastname: Lougheed
authors.forename: Simon A
authors.initials: SA
authors.lastname: Osborne
authors.forename: Barbara
authors.initials: B
authors.lastname: Saxty
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Smerdon
authors.forename: Debra L
authors.initials: DL
authors.lastname: Taylor
authors.forename: David
authors.initials: D
authors.lastname: Whalley
mesh_terms: D000588:Amines; D006801:Humans; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*; D011799:Quinazolines; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D051057:Proto-Oncogene Proteins c-akt; C030986:pyrimidine