title: Design of selective PI3Kα inhibitors starting from a promiscuous pan kinase scaffold.
abstract: Starting from compound 1, a potent PI3Kα inhibitor having poor general kinase selectivity, we used structural data and modelling to identify key exploitable differences between PI3Kα and the other kinases. This approach led us to design chemical modifications of the central pyrazole, which solved the poor kinase selectivity seen as a strong liability for the initial compound 1. Amongst the modifications explored, a 1,3,4-triazole ring (as in compound 4) as a replacement of the initial pyrazole provided good potency against PI3Kα, with excellent kinase selectivity.
authors.affiliation: AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom. Electronic address: bernard.barlaam2@astrazeneca.com.
authors.forename: Bernard
authors.initials: B
authors.lastname: Barlaam
authors.affiliation: AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Sabina
authors.initials: S
authors.lastname: Cosulich
authors.affiliation: AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Martina
authors.initials: M
authors.lastname: Fitzek
authors.affiliation: AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Green
authors.affiliation: AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France.
authors.forename: Craig S
authors.initials: CS
authors.lastname: Harris
authors.affiliation: AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Kevin
authors.initials: K
authors.lastname: Hudson
authors.affiliation: AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Lambert-van der Brempt
authors.affiliation: AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Ouvry
authors.affiliation: AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Ken
authors.initials: K
authors.lastname: Page
authors.affiliation: AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Linette
authors.initials: L
authors.lastname: Ruston
authors.affiliation: AstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Lara
authors.initials: L
authors.lastname: Ward
authors.affiliation: AstraZeneca, Centre de Recherches, Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims Cedex 2, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Delouvrié
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D014408:Biomarkers, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D004791:Enzyme Inhibitors; D050505:Mutant Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011720:Pyrazoles; D014230:Triazoles; C484760:PIK3CA protein, human
keywords: Kinase selectivity; PI3Kα inhibitor