title: Fragment-Based Drug Design of Novel Pyranopyridones as Cell Active and Orally Bioavailable Tankyrase Inhibitors.
abstract: Tankyrase activity has been linked to the regulation of intracellular axin levels, which have been shown to be crucial for the Wnt pathway. Deregulated Wnt signaling is important for the genesis of many diseases including cancer. We describe herein the discovery and development of a new series of tankyrase inhibitors. These pyranopyridones are highly active in various cell-based assays. A fragment/structure based optimization strategy led to a compound with good pharmacokinetic properties that is suitable for in vivo studies and further development.
authors.affiliation: Discovery Chemistry, Non-clinical Safety, Discovery Technologies, and Discovery Oncology, Small Molecule Research, Pharma Research & Early Development, Hoffmann-La Roche Inc. , pRED, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Javier
authors.initials: J
authors.lastname: de Vicente
authors.affiliation: Discovery Chemistry, Non-clinical Safety, Discovery Technologies, and Discovery Oncology, Small Molecule Research, Pharma Research & Early Development, Hoffmann-La Roche Inc. , pRED, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Parcharee
authors.initials: P
authors.lastname: Tivitmahaisoon
authors.affiliation: Discovery Chemistry, Non-clinical Safety, Discovery Technologies, and Discovery Oncology, Small Molecule Research, Pharma Research & Early Development, Hoffmann-La Roche Inc. , pRED, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Pamela
authors.initials: P
authors.lastname: Berry
authors.affiliation: Discovery Chemistry, Non-clinical Safety, Discovery Technologies, and Discovery Oncology, Small Molecule Research, Pharma Research & Early Development, Hoffmann-La Roche Inc. , pRED, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: David R
authors.initials: DR
authors.lastname: Bolin
authors.affiliation: Discovery Chemistry, Non-clinical Safety, Discovery Technologies, and Discovery Oncology, Small Molecule Research, Pharma Research & Early Development, Hoffmann-La Roche Inc. , pRED, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Daisy
authors.initials: D
authors.lastname: Carvajal
authors.affiliation: Discovery Chemistry, Non-clinical Safety, Discovery Technologies, and Discovery Oncology, Small Molecule Research, Pharma Research & Early Development, Hoffmann-La Roche Inc. , pRED, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: He
authors.affiliation: Discovery Chemistry, Non-clinical Safety, Discovery Technologies, and Discovery Oncology, Small Molecule Research, Pharma Research & Early Development, Hoffmann-La Roche Inc. , pRED, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Kuo-Sen
authors.initials: KS
authors.lastname: Huang
authors.affiliation: Discovery Chemistry, Non-clinical Safety, Discovery Technologies, and Discovery Oncology, Small Molecule Research, Pharma Research & Early Development, Hoffmann-La Roche Inc. , pRED, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Janson
authors.affiliation: Discovery Chemistry, Non-clinical Safety, Discovery Technologies, and Discovery Oncology, Small Molecule Research, Pharma Research & Early Development, Hoffmann-La Roche Inc. , pRED, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Lena
authors.initials: L
authors.lastname: Liang
authors.affiliation: Discovery Chemistry, Non-clinical Safety, Discovery Technologies, and Discovery Oncology, Small Molecule Research, Pharma Research & Early Development, Hoffmann-La Roche Inc. , pRED, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Christine
authors.initials: C
authors.lastname: Lukacs
authors.affiliation: Discovery Chemistry, Non-clinical Safety, Discovery Technologies, and Discovery Oncology, Small Molecule Research, Pharma Research & Early Development, Hoffmann-La Roche Inc. , pRED, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Ann
authors.initials: A
authors.lastname: Petersen
authors.affiliation: Discovery Chemistry, Non-clinical Safety, Discovery Technologies, and Discovery Oncology, Small Molecule Research, Pharma Research & Early Development, Hoffmann-La Roche Inc. , pRED, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Qian
authors.affiliation: Discovery Chemistry, Non-clinical Safety, Discovery Technologies, and Discovery Oncology, Small Molecule Research, Pharma Research & Early Development, Hoffmann-La Roche Inc. , pRED, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Lin
authors.initials: L
authors.lastname: Yi
authors.affiliation: Discovery Chemistry, Non-clinical Safety, Discovery Technologies, and Discovery Oncology, Small Molecule Research, Pharma Research & Early Development, Hoffmann-La Roche Inc. , pRED, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhuang
authors.affiliation: Discovery Chemistry, Non-clinical Safety, Discovery Technologies, and Discovery Oncology, Small Molecule Research, Pharma Research & Early Development, Hoffmann-La Roche Inc. , pRED, 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Johannes C
authors.initials: JC
authors.lastname: Hermann
keywords: Tankyrase inhibitor; Wnt; axin; fragment based drug design; oncology; structure based drug design