title: Discovery of imidazo[1,2-a]-pyridine inhibitors of pan-PI3 kinases that are efficacious in a mouse xenograft model.
abstract: Alterations in PI3K/AKT signaling are known to be implicated with tumorigenesis. The PI3 kinases family of lipid kinases has been an attractive therapeutic target for cancer treatment. Imidazopyridine compound 1, a potent, selective, and orally available pan-PI3K inhibitor, identified by scaffold morphing of a benzothiazole hit, was further optimized in order to achieve efficacy in a PTEN-deleted A2780 ovarian cancer mouse xenograft model. With a hypothesis that a planar conformation between the core and the 6-heteroaryl ring will allow for the accommodation of larger 5'-substituents in a hydrophobic area under P-loop, SAR efforts focused on 5'-alkoxy heteroaryl rings at the 6-position of imidazopyridine and imidazopyridazine cores that have the same dihedral angle of zero degrees. 6'-Alkoxy 5'-aminopyrazines in the imidazopyridine series were identified as the most potent compounds in the A2780 cell line. Compound 14 with 1,1,1-trifluoroisopropoxy group at 6'-position demonstrated excellent potency and selectivity, good oral exposure in rats and in vivo efficacy in A2780 tumor-bearing mouse. Also, we disclose the X-ray co-crystal structure of one enantiomer of compound 14 in PI3Kα, confirming that the trifluoromethyl group fits nicely in the hydrophobic hot spot under P-loop.
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States.
authors.forename: Wooseok
authors.initials: W
authors.lastname: Han
authors.affiliation: Oncology, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Menezes
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States.
authors.forename: Yongjin
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Knapp
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Elling
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Burger
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States.
authors.forename: Zhi-Jie
authors.initials: ZJ
authors.lastname: Ni
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States.
authors.forename: Aaron
authors.initials: A
authors.lastname: Smith
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States.
authors.forename: Jiong
authors.initials: J
authors.lastname: Lan
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States.
authors.forename: Teresa E
authors.initials: TE
authors.lastname: Williams
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States.
authors.forename: Joelle
authors.initials: J
authors.lastname: Verhagen
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States.
authors.forename: Kay
authors.initials: K
authors.lastname: Huh
authors.affiliation: Oncology, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States.
authors.forename: Hanne
authors.initials: H
authors.lastname: Merritt
authors.affiliation: Oncology, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States.
authors.forename: John
authors.initials: J
authors.lastname: Chan
authors.affiliation: Oncology, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States.
authors.forename: Susan
authors.initials: S
authors.lastname: Kaufman
authors.affiliation: Oncology, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States.
authors.forename: Charles F
authors.initials: CF
authors.lastname: Voliva
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States.
authors.forename: Sabina
authors.initials: S
authors.lastname: Pecchi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006207:Half-Life; D064593:Heterografts; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C001439:imidazo(1,2-a)pyridine
keywords: Cancer; Dihedral angle; Imidazopyridine; Lipid kinases; PI3K; Pan-PI3 kinase inhibitor; Pan-PI3 kinases