title: Discovery of a novel tricyclic 4H-thiazolo[5',4':4,5]pyrano[2,3-c]pyridine-2-amino scaffold and its application in a PI3Kα inhibitor with high PI3K isoform selectivity and potent cellular activity.
abstract: A novel, previously undescribed 4H-thiazolo[5',4':4,5]pyrano[2,3-c]pyridine tricyclic scaffold has been discovered. The application of this novel chemotype leading to a potent and selective prototype PI3Kα inhibitor with favorable physicochemical and PK-properties is described.
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, WKL-136.4.84, CH-4002 Basel, Switzerland. Electronic address: marc.gerspacher@novartis.com.
authors.forename: Marc
authors.initials: M
authors.lastname: Gerspacher
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, WKL-136.4.84, CH-4002 Basel, Switzerland.
authors.forename: Robin A
authors.initials: RA
authors.lastname: Fairhurst
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, WKL-136.4.84, CH-4002 Basel, Switzerland.
authors.forename: Robert
authors.initials: R
authors.lastname: Mah
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, WKL-136.4.84, CH-4002 Basel, Switzerland.
authors.forename: Esther
authors.initials: E
authors.lastname: Roehn-Carnemolla
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, WKL-136.4.84, CH-4002 Basel, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Furet
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, WKL-136.4.84, CH-4002 Basel, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Fritsch
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, WKL-136.4.84, CH-4002 Basel, Switzerland.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Guthy
mesh_terms: D000586:Amination; D000818:Animals; D058534:Class I Phosphatidylinositol 3-Kinases; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013844:Thiazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D013844:Thiazoles; C484760:PIK3CA protein, human
keywords: 4H-Thiazolo[5′,4′:4,5]pyrano[2,3-c]pyridine-2-amino derivative; Oncology; Phosphatidylinositol-3-kinase (PI3K); Selective PI3Kα Inhibitor