Identification and optimisation of a 4′,5-bisthiazole series of selective phosphatidylinositol-3 kinase alpha inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 25; no. 17; pp. 3569 - 3574
• Main Authors: Fairhurst, Robin A., Imbach-Weese, Patricia, Gerspacher, Marc, Caravatti, Giorgio, Furet, Pascal, Zoller, Thomas, Fritsch, Christine, Haasen, Dorothea, Trappe, Joerg, Guthy, Daniel A., Arz, Dorothee, Wirth, Jasmin
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.09.2015; Elsevier
• Subjects: Animals; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Class I Phosphatidylinositol 3-Kinases; Humans; Kinase inhibitor; Life Sciences & Biomedicine; Models, Molecular; Molecular Dynamics Simulation; Oncology; Pharmacology & Pharmacy; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - chemistry; Phosphatidylinositol 3-Kinases - metabolism; Phosphatidylinositol-3-kinase-alpha; Phosphatidylinositols; Physical Sciences; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Science & Technology; Thiazoles - chemistry; Thiazoles - pharmacology; Urea - analogs & derivatives; Urea - pharmacology; Oncology; Kinase inhibitor; Phosphatidylinositol-3-kinase-alpha; P110-ALPHA; POTENT; 3-KINASE; PATHWAY; GROWTH; CANCER; DISCOVERY
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2015.06.078

[Display omitted] Exploring the affinity-pocket binding moiety of a 2-aminothiazole (S)-proline-amide-urea series of selective PI3Kα inhibitors using a parallel-synthesis approach led to the identification of a novel 4′,5-bisthiazole sub-series. The synthesis and optimisation of both the affinity pocket and (S)-proline amide moieties within this 4′,5-bisthiazole sub-series are described. From this work a number of analogues, including 14 (A66) and 24, were identified as potent and selective PI3Kα inhibitor in vitro tool compounds.