title: Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist.
abstract: The blockade of aberrant hedgehog (Hh) signaling has shown promise for therapeutic intervention in cancer. A cell-based phenotypic high-throughput screen was performed, and the lead structure (1) was identified as an inhibitor of the Hh pathway via antagonism of the Smoothened receptor (Smo). Structure-activity relationship studies led to the discovery of a potent and specific Smoothened antagonist N-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyl-4'-(trifluoromethoxy)biphenyl-3-carboxamide (5m, NVP-LDE225), which is currently in clinical development.
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121.
authors.forename: Shifeng
authors.initials: S
authors.lastname: Pan
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121.
authors.forename: Xu
authors.initials: X
authors.lastname: Wu
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121.
authors.forename: Jiqing
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121.
authors.forename: Wenqi
authors.initials: W
authors.lastname: Gao
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121.
authors.forename: Yongqin
authors.initials: Y
authors.lastname: Wan
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121.
authors.forename: Dai
authors.initials: D
authors.lastname: Cheng
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121.
authors.forename: Dong
authors.initials: D
authors.lastname: Han
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121.
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Englund
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Novartis Institute for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139.
authors.forename: Stefan
authors.initials: S
authors.lastname: Peukert
authors.affiliation: Novartis Institute for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139.
authors.forename: Karen
authors.initials: K
authors.lastname: Miller-Moslin
authors.affiliation: Novartis Institute for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139.
authors.forename: Jing
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Novartis Institute for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139.
authors.forename: Ribo
authors.initials: R
authors.lastname: Guo
authors.affiliation: Novartis Institute for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139.
authors.forename: Melissa
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Novartis Institute for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139.
authors.forename: Anthony
authors.initials: A
authors.lastname: Vattay
authors.affiliation: Novartis Institute for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139.
authors.forename: Yun
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Novartis Institute for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Tsao
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121.
authors.forename: Fangxian
authors.initials: F
authors.lastname: Sun
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121.
authors.forename: AnneMarie C
authors.initials: AC
authors.lastname: Pferdekamper
authors.affiliation: Novartis Institute for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dodd
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121.
authors.forename: Tove
authors.initials: T
authors.lastname: Tuntland
authors.affiliation: Novartis Institute for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139.
authors.forename: Wieslawa
authors.initials: W
authors.lastname: Maniara
authors.affiliation: Novartis Institute for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Kelleher
authors.affiliation: Novartis Institute for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139.
authors.forename: Yung-Mae
authors.initials: YM
authors.lastname: Yao
authors.affiliation: Novartis Institute for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139.
authors.forename: Markus
authors.initials: M
authors.lastname: Warmuth
authors.affiliation: Novartis Institute for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139.
authors.forename: Juliet
authors.initials: J
authors.lastname: Williams
authors.affiliation: Novartis Institute for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139.
authors.forename: Marion
authors.initials: M
authors.lastname: Dorsch
keywords: Hedgehog signaling pathway; Smoothened; medulloblastoma