Literature DB >> 24900187

Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist.

Shifeng Pan1, Xu Wu1, Jiqing Jiang1, Wenqi Gao1, Yongqin Wan1, Dai Cheng1, Dong Han1, Jun Liu1, Nathan P Englund1, Yan Wang1, Stefan Peukert2, Karen Miller-Moslin2, Jing Yuan2, Ribo Guo2, Melissa Matsumoto2, Anthony Vattay2, Yun Jiang2, Jeffrey Tsao2, Fangxian Sun1, AnneMarie C Pferdekamper1, Stephanie Dodd2, Tove Tuntland1, Wieslawa Maniara2, Joseph F Kelleher2, Yung-Mae Yao2, Markus Warmuth2, Juliet Williams2, Marion Dorsch2.   

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.

Entities:  

Keywords:  Hedgehog signaling pathway; Smoothened; medulloblastoma

Year:  2010        PMID： 24900187      PMCID： PMC4007689          DOI： 10.1021/ml1000307

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  19 in total

Review 1.  Hedgehog signaling in animal development: paradigms and principles.

Authors:  P W Ingham; A P McMahon
Journal:  Genes Dev       Date:  2001-12-01       Impact factor: 11.361

Review 2.  Developmental roles and clinical significance of hedgehog signaling.

Authors:  Andrew P McMahon; Philip W Ingham; Clifford J Tabin
Journal:  Curr Top Dev Biol       Date:  2003       Impact factor: 4.897

3.  The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog.

Authors:  D M Stone; M Hynes; M Armanini; T A Swanson; Q Gu; R L Johnson; M P Scott; D Pennica; A Goddard; H Phillips; M Noll; J E Hooper; F de Sauvage; A Rosenthal
Journal:  Nature       Date:  1996-11-14       Impact factor: 49.962

4.  Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/-)p53(-/-) mice.

Authors:  Justyna T Romer; Hiromichi Kimura; Susan Magdaleno; Ken Sasai; Christine Fuller; Helen Baines; Michele Connelly; Clinton F Stewart; Stephen Gould; Lee L Rubin; Tom Curran
Journal:  Cancer Cell       Date:  2004-09       Impact factor: 31.743

5.  Medulloblastoma growth inhibition by hedgehog pathway blockade.

Authors:  David M Berman; Sunil S Karhadkar; Andrew R Hallahan; Joel I Pritchard; Charles G Eberhart; D Neil Watkins; James K Chen; Michael K Cooper; Jussi Taipale; James M Olson; Philip A Beachy
Journal:  Science       Date:  2002-08-30       Impact factor: 47.728

6.  GDC-0449-a potent inhibitor of the hedgehog pathway.

Authors:  Kirk D Robarge; Shirley A Brunton; Georgette M Castanedo; Yong Cui; Michael S Dina; Richard Goldsmith; Stephen E Gould; Oivin Guichert; Janet L Gunzner; Jason Halladay; Wei Jia; Cyrus Khojasteh; Michael F T Koehler; Karen Kotkow; Hank La; Rebecca L Lalonde; Kevin Lau; Leslie Lee; Derek Marshall; James C Marsters; Lesley J Murray; Changgeng Qian; Lee L Rubin; Laurent Salphati; Mark S Stanley; John H A Stibbard; Daniel P Sutherlin; Savita Ubhayaker; Shumei Wang; Susan Wong; Minli Xie
Journal:  Bioorg Med Chem Lett       Date:  2009-08-15       Impact factor: 2.823

7.  Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome.

Authors:  H Hahn; C Wicking; P G Zaphiropoulous; M R Gailani; S Shanley; A Chidambaram; I Vorechovsky; E Holmberg; A B Unden; S Gillies; K Negus; I Smyth; C Pressman; D J Leffell; B Gerrard; A M Goldstein; M Dean; R Toftgard; G Chenevix-Trench; B Wainwright; A E Bale
Journal:  Cell       Date:  1996-06-14       Impact factor: 41.582

8.  1-amino-4-benzylphthalazines as orally bioavailable smoothened antagonists with antitumor activity.

Authors:  Karen Miller-Moslin; Stefan Peukert; Rishi K Jain; Michael A McEwan; Rajesh Karki; Luis Llamas; Naeem Yusuff; Feng He; Yanhong Li; Yingchuan Sun; Miao Dai; Lawrence Perez; Walter Michael; Tao Sheng; Huangshu Lei; Rui Zhang; Juliet Williams; Aaron Bourret; Arun Ramamurthy; Jing Yuan; Ribo Guo; Melissa Matsumoto; Anthony Vattay; Wieslawa Maniara; Adam Amaral; Marion Dorsch; Joseph F Kelleher
Journal:  J Med Chem       Date:  2009-07-09       Impact factor: 7.446

9.  Inhibition of the hedgehog pathway in advanced basal-cell carcinoma.

Authors:  Daniel D Von Hoff; Patricia M 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 M Mackey; Bertram L Lum; Walter C Darbonne; James C Marsters; Frederic J de Sauvage; Jennifer A Low
Journal:  N Engl J Med       Date:  2009-09-02       Impact factor: 91.245

Review 10.  Hedgehog checkpoints in medulloblastoma: the chromosome 17p deletion paradigm.

Authors:  Elisabetta Ferretti; Enrico De Smaele; Lucia Di Marcotullio; Isabella Screpanti; Alberto Gulino
Journal:  Trends Mol Med       Date:  2005-11-14       Impact factor: 11.951
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  105 in total

1.  Hedgehog pathway blockade with the cancer drug LDE225 disrupts taste organs and taste sensation.

Authors:  Archana Kumari; Alexandre N Ermilov; Benjamin L Allen; Robert M Bradley; Andrzej A Dlugosz; Charlotte M Mistretta
Journal:  J Neurophysiol       Date:  2014-11-12       Impact factor: 2.714

2.  Loss of the tumor suppressor Snf5 leads to aberrant activation of the Hedgehog-Gli pathway.

Authors:  Zainab Jagani; E Lorena Mora-Blanco; Courtney G Sansam; Elizabeth S McKenna; Boris Wilson; Dongshu Chen; Justin Klekota; Pablo Tamayo; Phuong T L Nguyen; Michael Tolstorukov; Peter J Park; Yoon-Jae Cho; Kathy Hsiao; Silvia Buonamici; Scott L Pomeroy; Jill P Mesirov; Heinz Ruffner; Tewis Bouwmeester; Sarah J Luchansky; Joshua Murtie; Joseph F Kelleher; Markus Warmuth; William R Sellers; Charles W M Roberts; Marion Dorsch
Journal:  Nat Med       Date:  2010-11-14       Impact factor: 53.440

Review 3.  Synthetic Small Molecule Inhibitors of Hh Signaling As Anti-Cancer Chemotherapeutics.

Authors:  C A Maschinot; J R Pace; M K Hadden
Journal:  Curr Med Chem       Date:  2015       Impact factor: 4.530

Review 4.  Matching mice to malignancy: molecular subgroups and models of medulloblastoma.

Authors:  Jasmine Lau; Christin Schmidt; Shirley L Markant; Michael D Taylor; Robert J Wechsler-Reya; William A Weiss
Journal:  Childs Nerv Syst       Date:  2012-04       Impact factor: 1.475

5.  Sonic Hedgehog and WNT Signaling Promote Adrenal Gland Regeneration in Male Mice.

Authors:  Isabella Finco; Antonio M Lerario; Gary D Hammer
Journal:  Endocrinology       Date:  2018-02-01       Impact factor: 4.736

6.  Dual Inhibition of Hedgehog and c-Met Pathways for Pancreatic Cancer Treatment.

Authors:  Agnieszka A Rucki; Qian Xiao; Stephen Muth; Jianlin Chen; Xu Che; Jennifer Kleponis; Rajni Sharma; Robert A Anders; Elizabeth M Jaffee; Lei Zheng
Journal:  Mol Cancer Ther       Date:  2017-09-01       Impact factor: 6.261

Review 7.  Safety and Tolerability of Sonic Hedgehog Pathway Inhibitors in Cancer.

Authors:  Richard L Carpenter; Haimanti Ray
Journal:  Drug Saf       Date:  2019-02       Impact factor: 5.606

8.  Exposure-QT analysis for sonidegib (LDE225), an oral inhibitor of the hedgehog signaling pathway, for measures of the QT prolongation potential in healthy subjects and in patients with advanced solid tumors.

Authors:  Michelle Quinlan; Jocelyn Zhou; Eunju Hurh; Dalila Sellami
Journal:  Eur J Clin Pharmacol       Date:  2016-09-23       Impact factor: 2.953

Review 9.  Differential role of Hedgehog signaling in human pancreatic (patho-) physiology: An up to date review.

Authors:  Eckhard Klieser; Stefan Swierczynski; Christian Mayr; Tarkan Jäger; Johanna Schmidt; Daniel Neureiter; Tobias Kiesslich; Romana Illig
Journal:  World J Gastrointest Pathophysiol       Date:  2016-05-15

10.  Identification of a novel Smoothened antagonist that potently suppresses Hedgehog signaling.

Authors:  Jiangbo Wang; Robert A Mook; Jiuyi Lu; David M Gooden; Anthony Ribeiro; Anchen Guo; Larry S Barak; H Kim Lyerly; Wei Chen
Journal:  Bioorg Med Chem       Date:  2012-09-23       Impact factor: 3.641
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