Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist
Shifeng Pan,Xu Wu,Jiqing Jiang,Wenqi Gao,Yongqin Wan,Dai Cheng,Dong Han,Jun Liu,Nathan P. Englund,Yan Wang,Stefan Peukert,Karen Miller-Moslin,Jing Yuan,Ribo Guo,Melissa Matsumoto,Anthony Vattay,Yun Jiang,Jeffrey Tsao,Fangxian Sun,AnneMarie Culazzo Pferdekamper,Stephanie Kay Dodd,Tove Tuntland,Wieslawa Maniara,Joseph Kelleher,Yung-mae Yao,Markus Warmuth,Juliet Williams,Marion Dorsch +27 more
TLDR
Structural-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.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.read more
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Targeting cancer stem cell pathways for cancer therapy
Liqun Yang,Pengfei Shi,Gaichao Zhao,Jie Xu,Wen Peng,Jiayi Zhang,Guanghui Zhang,Xiaowen Wang,Zhen Dong,Fei Chen,Hongjuan Cui +10 more
TL;DR: Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials.
Journal ArticleDOI
Interfering with Resistance to Smoothened Antagonists by Inhibition of the PI3K Pathway in Medulloblastoma
Silvia Buonamici,Juliet Williams,Michael Morrissey,Anlai Wang,Ribo Guo,Anthony Vattay,Kathy Hsiao,Jing Yuan,John Green,Beatriz Ospina,Qunyan Yu,Lance Ostrom,Paul Fordjour,Dustin L. Anderson,John Monahan,Joseph Kelleher,Stefan Peukert,Shifeng Pan,Xu Wu,Sauveur Michel Maira,Carlos Garcia-Echeverria,Kimberly J. Briggs,D. Neil Watkins,Yung Mae Yao,Christoph Lengauer,Markus Warmuth,William R. Sellers,Marion Dorsch +27 more
TL;DR: By identifying a drug combination that delays or even combats development of resistance when used as a first-line treatment in clinical trials, these results could ultimately improve the lives of patients with medulloblastoma or other cancers that depend on Smo for their survival.
Journal ArticleDOI
Targeting the Sonic Hedgehog Signaling Pathway: Review of Smoothened and GLI Inhibitors
TL;DR: The sonic hedgehog (Shh) signaling pathway is a major regulator of cell differentiation, cell proliferation, and tissue polarity and the current landscape of the Shh-SMO-GLI pathway inhibitors including those in preclinical studies and clinical trials is detailed.
Journal ArticleDOI
Recent advances in the trifluoromethylation methodology and new CF3-containing drugs
Wei Zhu,Jiang Wang,Shuni Wang,Zhanni Gu,José Luis Aceña,Kunisuke Izawa,Hong Liu,Vadim A. Soloshonok,Vadim A. Soloshonok +8 more
TL;DR: A brief assessment of the methodological field of trifluoromethylation and its possible impact on the development of new CF 3 -containing pharmaceuticals is provided in this paper.
Journal ArticleDOI
Itraconazole and Arsenic Trioxide Inhibit Hedgehog Pathway Activation and Tumor Growth Associated with Acquired Resistance to Smoothened Antagonists
James Kim,Blake T. Aftab,Blake T. Aftab,Jean Y. Tang,Jean Y. Tang,Daniel H. Kim,Alexander Lee,Alexander Lee,Melika Rezaee,Jynho Kim,Baozhi Chen,Emily M. King,Alexandra Borodovsky,Gregory J. Riggins,Ervin H. Epstein,Philip A. Beachy,Charles M. Rudin +16 more
TL;DR: It is reported that itraconazole and arsenic trioxide, two agents in clinical use that inhibit Hedgehog signaling by mechanisms distinct from that of current Smoothened antagonists, retain inhibitory activity in vitro in the context of all reported resistance-conferring Smothened mutants and GLI2 overexpression.
References
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Hedgehog signaling in animal development: paradigms and principles.
TL;DR: In their screen for mutations that disrupt the Drosophila larval body plan, these authors identified several that cause the duplication of denticles and an accompanying loss of naked cuticle, characteristic of the posterior half of each segment.
Journal ArticleDOI
Mutations of the Human Homolog of Drosophila patched in the Nevoid Basal Cell Carcinoma Syndrome
Heidi Hahn,Carol Wicking,Peter G. Zaphiropoulos,Mae R. Gailani,Susan Shanley,Abirami Chidambaram,Igor Vorechovsky,Erika Holmberg,Anne Birgitte Undén,Susan Gillies,Kylie Negus,Ian M. Smyth,Carolyn Pressman,David J. Leffell,Bernard Gerrard,Alisa M. Goldstein,Michael Dean,Rune Toftgård,Georgia Chenevix-Trench,Brandon J. Wainwright,Allen E. Bale +20 more
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Journal ArticleDOI
Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened.
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Journal ArticleDOI
The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog
Donna M. Stone,Mary Hynes,Mark Armanini,Todd A. Swanson,Qimin Gu,Ronald L. Johnson,Matthew P. Scott,Diane Pennica,Audrey Goddard,Heidi S. Phillips,Markus Noll,Joan E. Hooper,Frederic J. de Sauvage,Arnon Rosenthal +13 more
TL;DR: It is shown that Re can form a physical complex with a newly cloned vertebrate homologue of the Drosophila protein Smoothened (vSmo), and that vSmo is coexpressed with vPtc in many tissues but does not bind Shh directly.
Journal ArticleDOI
Inhibition of the Hedgehog Pathway in Advanced Basal-Cell Carcinoma
Daniel D. Von Hoff,Patricia LoRusso,Charles M. Rudin,Josina C. Reddy,Robert L. Yauch,Raoul Tibes,Glen J. Weiss,Mitesh J. Borad,Christine L. Hann,Julie R. Brahmer,Howard Mackey,Bertram L. Lum,Walter C. Darbonne,James C. Marsters,Frederic J. de Sauvage,Jennifer A. Low +15 more
TL;DR: GDC-0449, an orally active small molecule that targets the hedgehog pathway, appears to have antitumor activity in locally advanced or metastatic basal-cell carcinoma.
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