Literature DB >> 24900436

Discovery of PF-04449913, a Potent and Orally Bioavailable Inhibitor of Smoothened.

Michael J Munchhof1, Qifang Li2, Andrei Shavnya2, Gary V Borzillo2, Tracey L Boyden2, Christopher S Jones3, Susan D LaGreca4, Luis Martinez-Alsina2, Nandini Patel2, Kathleen Pelletier2, Larry A Reiter5, Michael D Robbins6, George T Tkalcevic2.   

Abstract

Inhibitors of the Hedgehog signaling pathway have generated a great deal of interest in the oncology area due to the mounting evidence of their potential to provide promising therapeutic options for patients. Herein, we describe the discovery strategy to overcome the issues inherent in lead structure 1 that resulted in the identification of Smoothened inhibitor 1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea (PF-04449913, 26), which has been advanced to human clinical studies.

Entities:  

Keywords:  Hedgehog signaling pathway; PF-04449913; Smoothened

Year:  2011        PMID： 24900436      PMCID： PMC4025788          DOI： 10.1021/ml2002423

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


  14 in total

1.  Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: An examination of in vitro half-life approach and nonspecific binding to microsomes.

Authors:  R S Obach
Journal:  Drug Metab Dispos       Date:  1999-11       Impact factor: 3.922

2.  Physiochemical drug properties associated with in vivo toxicological outcomes.

Authors:  Jason D Hughes; Julian Blagg; David A Price; Simon Bailey; Gary A Decrescenzo; Rajesh V Devraj; Edmund Ellsworth; Yvette M Fobian; Michael E Gibbs; Richard W Gilles; Nigel Greene; Enoch Huang; Teresa Krieger-Burke; Jens Loesel; Travis Wager; Larry Whiteley; Yao Zhang
Journal:  Bioorg Med Chem Lett       Date:  2008-07-24       Impact factor: 2.823

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

Authors:  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 C Pferdekamper; Stephanie Dodd; Tove Tuntland; Wieslawa Maniara; Joseph F Kelleher; Yung-Mae Yao; Markus Warmuth; Juliet Williams; Marion Dorsch
Journal:  ACS Med Chem Lett       Date:  2010-03-16       Impact factor: 4.345

Review 4.  Small-molecule inhibitors of the hedgehog signaling pathway as cancer therapeutics.

Authors:  Stefan Peukert; Karen Miller-Moslin
Journal:  ChemMedChem       Date:  2010-04-06       Impact factor: 3.466

Review 5.  Modulators of the hedgehog signaling pathway.

Authors:  Philipp Heretsch; Lito Tzagkaroulaki; Athanassios Giannis
Journal:  Bioorg Med Chem       Date:  2010-07-23       Impact factor: 3.641

Review 6.  Hedgehog signaling in development and cancer.

Authors:  Jin Jiang; Chi-Chung Hui
Journal:  Dev Cell       Date:  2008-12       Impact factor: 12.270

Review 7.  Salt formation to improve drug solubility.

Authors:  Abu T M Serajuddin
Journal:  Adv Drug Deliv Rev       Date:  2007-05-29       Impact factor: 15.470

8.  The hedgehog pathway inhibitor GDC-0449 shows potential in skin and other cancers.

Authors:  Sheila A Doggrell
Journal:  Expert Opin Investig Drugs       Date:  2010-03       Impact factor: 6.206

9.  Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine.

Authors:  J Taipale; J K Chen; M K Cooper; B Wang; R K Mann; L Milenkovic; M P Scott; P A Beachy
Journal:  Nature       Date:  2000-08-31       Impact factor: 49.962

10.  Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists.

Authors:  Maria Frank-Kamenetsky; Xiaoyan M Zhang; Steve Bottega; Oivin Guicherit; Hynek Wichterle; Henryk Dudek; David Bumcrot; Frank Y Wang; Simon Jones; Janine Shulok; Lee L Rubin; Jeffery A Porter
Journal:  J Biol       Date:  2002-11-06
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  49 in total

Review 1.  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 2.  Pharmacotherapeutic Targeting of G Protein-Coupled Receptors in Oncology: Examples of Approved Therapies and Emerging Concepts.

Authors:  Rosamaria Lappano; Marcello Maggiolini
Journal:  Drugs       Date:  2017-06       Impact factor: 9.546

3.  Glasdegib as maintenance therapy for patients with AML and MDS patients at high risk for postallogeneic stem cell transplant relapse.

Authors:  Andrew Kent; Sumithira Vasu; Derek Schatz; Natalie Monson; Steven Devine; Clayton Smith; Jonathan A Gutman; Daniel A Pollyea
Journal:  Blood Adv       Date:  2020-07-14

Review 4.  Development of anticancer agents targeting the Hedgehog signaling.

Authors:  Xiangqian Zhang; Ye Tian; Yanling Yang; Jijun Hao
Journal:  Cell Mol Life Sci       Date:  2017-03-17       Impact factor: 9.261

5.  Evaluation of the effect of rifampin on the pharmacokinetics of the Smoothened inhibitor glasdegib in healthy volunteers.

Authors:  M Naveed Shaik; Brian Hee; Hua Wei; Robert R LaBadie
Journal:  Br J Clin Pharmacol       Date:  2018-04-10       Impact factor: 4.335

6.  Formulation and evaluation of itraconazole liposomes for Hedgehog pathway inhibition.

Authors:  Jennifer R Pace; Rajan Jog; Diane J Burgess; M Kyle Hadden
Journal:  J Liposome Res       Date:  2019-10-02       Impact factor: 3.648

Review 7.  Hedgehog Signaling: From Basic Biology to Cancer Therapy.

Authors:  Fujia Wu; Yu Zhang; Bo Sun; Andrew P McMahon; Yu Wang
Journal:  Cell Chem Biol       Date:  2017-03-09       Impact factor: 8.116

Review 8.  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

9.  Development of thieno- and benzopyrimidinone inhibitors of the Hedgehog signaling pathway reveals PDE4-dependent and PDE4-independent mechanisms of action.

Authors:  Jonathan E Hempel; Adrian G Cadar; Charles C Hong
Journal:  Bioorg Med Chem Lett       Date:  2016-03-07       Impact factor: 2.823

10.  The use of hedgehog antagonists in cancer therapy: a comparison of clinical outcomes and gene expression analyses.

Authors:  Burthia E Booker; Adam D Steg; Stefan Kovac; Charles N Landen; Hope M Amm
Journal:  Cancer Biol Ther       Date:  2020-09-11       Impact factor: 4.742
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