Literature DB >> 25589931

Pyrimidine-based tricyclic molecules as potent and orally efficacious inhibitors of wee1 kinase.

Yunsong Tong1, Maricel Torrent1, Alan S Florjancic1, Kenneth D Bromberg1, Fritz G Buchanan1, Debra C Ferguson1, Eric F Johnson1, Loren M Lasko1, David Maag1, Philip J Merta1, Amanda M Olson1, Donald J Osterling1, Nirupama Soni1, Alexander R Shoemaker1, Thomas D Penning1.   

Abstract

Aided by molecular modeling, compounds with a pyrimidine-based tricyclic scaffold were designed and confirmed to inhibit Wee1 kinase. Structure-activity studies identified key pharmacophores at the aminoaryl and halo-benzene regions responsible for binding affinity with sub-nM K i values. The potent inhibitors demonstrated sub-μM activities in both functional and mechanism-based cellular assays and also possessed desirable pharmacokinetic profiles. The lead molecule, 31, showed oral efficacy in potentiating the antiproliferative activity of irinotecan, a cytotoxic agent, in a NCI-H1299 mouse xenograft model.

Entities:  

Keywords:  Wee1 kinase inhibitors; antitumor

Year:  2014        PMID： 25589931      PMCID： PMC4291713          DOI： 10.1021/ml5002745

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


  14 in total

1.  WEE1 kinase targeting combined with DNA-damaging cancer therapy catalyzes mitotic catastrophe.

Authors:  Philip C De Witt Hamer; Shahryar E Mir; David Noske; Cornelis J F Van Noorden; Tom Würdinger
Journal:  Clin Cancer Res       Date:  2011-05-11       Impact factor: 12.531

2.  4-Phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione inhibitors of the checkpoint kinase Wee1. Structure-activity relationships for chromophore modification and phenyl ring substitution.

Authors:  Brian D Palmer; Andrew M Thompson; R John Booth; Ellen M Dobrusin; Alan J Kraker; Ho H Lee; Elizabeth A Lunney; Lorna H Mitchell; Daniel F Ortwine; Jeff B Smaill; Leesa M Swan; William A Denny
Journal:  J Med Chem       Date:  2006-08-10       Impact factor: 7.446

3.  Structure and inhibition of the human cell cycle checkpoint kinase, Wee1A kinase: an atypical tyrosine kinase with a key role in CDK1 regulation.

Authors:  Christopher J Squire; James M Dickson; Ivan Ivanovic; Edward N Baker
Journal:  Structure       Date:  2005-04       Impact factor: 5.006

4.  In silico analysis of kinase expression identifies WEE1 as a gatekeeper against mitotic catastrophe in glioblastoma.

Authors:  Shahryar E Mir; Philip C De Witt Hamer; Przemek M Krawczyk; Leonora Balaj; An Claes; Johanna M Niers; Angela A G Van Tilborg; Aeilko H Zwinderman; Dirk Geerts; Gertjan J L Kaspers; W Peter Vandertop; Jacqueline Cloos; Bakhos A Tannous; Pieter Wesseling; Jacob A Aten; David P Noske; Cornelis J F Van Noorden; Thomas Würdinger
Journal:  Cancer Cell       Date:  2010-09-14       Impact factor: 31.743

Review 5.  Death by releasing the breaks: CHK1 inhibitors as cancer therapeutics.

Authors:  Cynthia X Ma; James W Janetka; Helen Piwnica-Worms
Journal:  Trends Mol Med       Date:  2010-11-17       Impact factor: 11.951

Review 6.  WEE1 inhibition and genomic instability in cancer.

Authors:  Lianne E M Vriend; Philip C De Witt Hamer; Cornelis J F Van Noorden; Thomas Würdinger
Journal:  Biochim Biophys Acta       Date:  2013-05-31

7.  Synthesis and structure-activity relationships of N-6 substituted analogues of 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as inhibitors of Wee1 and Chk1 checkpoint kinases.

Authors:  Jeff B Smaill; Edward N Baker; R John Booth; Alexander J Bridges; James M Dickson; Ellen M Dobrusin; Ivan Ivanovic; Alan J Kraker; Ho H Lee; Elizabeth A Lunney; Daniel F Ortwine; Brian D Palmer; John Quin; Christopher J Squire; Andrew M Thompson; William A Denny
Journal:  Eur J Med Chem       Date:  2007-08-06       Impact factor: 6.514

8.  High expression of Wee1 is associated with poor disease-free survival in malignant melanoma: potential for targeted therapy.

Authors:  Gry Irene Magnussen; Ruth Holm; Elisabeth Emilsen; Anne Katrine Ree Rosnes; Ana Slipicevic; Vivi Ann Flørenes
Journal:  PLoS One       Date:  2012-06-12       Impact factor: 3.240

9.  Integrated functional, gene expression and genomic analysis for the identification of cancer targets.

Authors:  Elizabeth Iorns; Christopher J Lord; Anita Grigoriadis; Sarah McDonald; Kerry Fenwick; Alan Mackay; Charles A Mein; Rachael Natrajan; Kay Savage; Narinder Tamber; Jorge S Reis-Filho; Nicholas C Turner; Alan Ashworth
Journal:  PLoS One       Date:  2009-04-09       Impact factor: 3.240

10.  Discovery of gene expression-based pharmacodynamic biomarker for a p53 context-specific anti-tumor drug Wee1 inhibitor.

Authors:  Shinji Mizuarai; Kazunori Yamanaka; Hiraku Itadani; Tsuyoshi Arai; Toshihide Nishibata; Hiroshi Hirai; Hidehito Kotani
Journal:  Mol Cancer       Date:  2009-06-08       Impact factor: 27.401
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  2 in total

Review 1.  ATM, ATR, CHK1, CHK2 and WEE1 inhibitors in cancer and cancer stem cells.

Authors:  Cyril Ronco; Anthony R Martin; Luc Demange; Rachid Benhida
Journal:  Medchemcomm       Date:  2016-11-30       Impact factor: 3.597

Review 2.  Regulation of G2/M Transition by Inhibition of WEE1 and PKMYT1 Kinases.

Authors:  Matthias Schmidt; Alexander Rohe; Charlott Platzer; Abdulkarim Najjar; Frank Erdmann; Wolfgang Sippl
Journal:  Molecules       Date:  2017-11-23       Impact factor: 4.411
  2 in total

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