Literature DB >> 24900197

Discovery of a Potent, Injectable Inhibitor of Aurora Kinases Based on the Imidazo-[1,2-a]-Pyrazine Core.

Tao Yu1, Jayaram R Tagat1, Angela D Kerekes1, Ronald J Doll1, Yonglian Zhang1, Yushi Xiao1, Sara Esposite1, David B Belanger2, Patrick J Curran2, Amit K Mandal2, M Arshad Siddiqui2, Neng-Yang Shih2, Andrea D Basso3, Ming Liu3, Kimberly Gray3, Seema Tevar3, Jennifer Jones3, Suining Lee3, Lianzhu Liang3, Samad Ponery3, Elizabeth B Smith3, Alan Hruza4, Johannes Voigt4, Lata Ramanathan4, Winifred Prosise4, Mengwei Hu5.   

Abstract

The imidazo-[1,2-a]-pyrazine (1) is a dual inhibitor of Aurora kinases A and B with modest cell potency (IC50 = 250 nM) and low solubility (5 μM). Lead optimization guided by the binding mode led to the acyclic amino alcohol 12k (SCH 1473759), which is a picomolar inhibitor of Aurora kinases (TdF K d Aur A = 0.02 nM and Aur B = 0.03 nM) with improved cell potency (phos-HH3 inhibition IC50 = 25 nM) and intrinsic aqueous solubility (11.4 mM). It also demonstrated efficacy and target engagement in human tumor xenograft mouse models.

Entities:  

Keywords:  Aurora kinase inhibitors; SCH 1473759; aqueous solubility; cell potency; imidazo-[1,2-a]-pyrazine; tumor xenograft model

Year:  2010        PMID： 24900197      PMCID： PMC4007894          DOI： 10.1021/ml100063w

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


  10 in total

1.  Mitotic requirement for aurora A kinase is bypassed in the absence of aurora B kinase.

Authors:  Hui Yang; Teresa Burke; Jack Dempsey; Bruce Diaz; Elizabeth Collins; John Toth; Richard Beckmann; Xiang Ye
Journal:  FEBS Lett       Date:  2005-06-20       Impact factor: 4.124

Review 2.  Knowledge based prediction of ligand binding modes and rational inhibitor design for kinase drug discovery.

Authors:  Arup K Ghose; Torsten Herbertz; Douglas A Pippin; Joseph M Salvino; John P Mallamo
Journal:  J Med Chem       Date:  2008-08-19       Impact factor: 7.446

3.  Discovery of a potent and selective aurora kinase inhibitor.

Authors:  Johan D Oslob; Michael J Romanowski; Darin A Allen; Subramanian Baskaran; Minna Bui; Robert A Elling; William M Flanagan; Amy D Fung; Emily J Hanan; Shannon Harris; Stacey A Heumann; Ute Hoch; Jeffrey W Jacobs; Joni Lam; Chris E Lawrence; Robert S McDowell; Michelle A Nannini; Wang Shen; Jeffrey A Silverman; Michelle M Sopko; Bradley T Tangonan; Juli Teague; Josh C Yoburn; Chul H Yu; Min Zhong; Kristin M Zimmerman; Tom O'Brien; Willard Lew
Journal:  Bioorg Med Chem Lett       Date:  2008-07-24       Impact factor: 2.823

Review 4.  Discovery and development of aurora kinase inhibitors as anticancer agents.

Authors:  John R Pollard; Michael Mortimore
Journal:  J Med Chem       Date:  2009-05-14       Impact factor: 7.446

Review 5.  Through the "gatekeeper door": exploiting the active kinase conformation.

Authors:  Fabio Zuccotto; Elena Ardini; Elena Casale; Mauro Angiolini
Journal:  J Med Chem       Date:  2010-04-08       Impact factor: 7.446

6.  Screening for antibacterial inhibitors of the UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) using a high-throughput mass spectrometry assay.

Authors:  Erik F Langsdorf; Asra Malikzay; William A Lamarr; Dayna Daubaras; Cynthia Kravec; Rumin Zhang; Richard Hart; Frederick Monsma; Todd Black; Can C Ozbal; Lynn Miesel; Charles A Lunn
Journal:  J Biomol Screen       Date:  2009-12-17

7.  Discovery, synthesis, and in vivo activity of a new class of pyrazoloquinazolines as selective inhibitors of aurora B kinase.

Authors:  Andrew A Mortlock; Kevin M Foote; Nicola M Heron; Frédéric H Jung; Georges Pasquet; Jean-Jacques M Lohmann; Nicolas Warin; Fabrice Renaud; Chris De Savi; Nicola J Roberts; Trevor Johnson; Cyril B Dousson; George B Hill; David Perkins; Glenn Hatter; Robert W Wilkinson; Stephen R Wedge; Simon P Heaton; Rajesh Odedra; Nicholas J Keen; Claire Crafter; Elaine Brown; Katherine Thompson; Stephen Brightwell; Liz Khatri; Madeleine C Brady; Sarah Kearney; David McKillop; Steve Rhead; Tony Parry; Stephen Green
Journal:  J Med Chem       Date:  2007-03-21       Impact factor: 7.446

8.  SCH 1473759, a novel Aurora inhibitor, demonstrates enhanced anti-tumor activity in combination with taxanes and KSP inhibitors.

Authors:  Andrea D Basso; Ming Liu; Kimberly Gray; Seema Tevar; Suining Lee; Lianzhu Liang; Abdul Ponery; Elizabeth B Smith; Frederick J Monsma; Tao Yu; Yonglian Zhang; Angela D Kerekes; Sara Esposite; Yushi Xiao; Jayaram R Tagat; Daniel J Hicklin; Paul Kirschmeier
Journal:  Cancer Chemother Pharmacol       Date:  2011-02-05       Impact factor: 3.333

9.  A class of 2,4-bisanilinopyrimidine Aurora A inhibitors with unusually high selectivity against Aurora B.

Authors:  Ignacio Aliagas-Martin; Dan Burdick; Laura Corson; Jennafer Dotson; Jason Drummond; Carter Fields; Oscar W Huang; Thomas Hunsaker; Tracy Kleinheinz; Elaine Krueger; Jun Liang; John Moffat; Gail Phillips; Rebecca Pulk; Thomas E Rawson; Mark Ultsch; Leslie Walker; Christian Wiesmann; Birong Zhang; Bing-Yan Zhu; Andrea G Cochran
Journal:  J Med Chem       Date:  2009-05-28       Impact factor: 7.446

Review 10.  Aurora kinase inhibitors in preclinical and clinical testing.

Authors:  Chun Hei Antonio Cheung; Mohane Selvaraj Coumar; Hsing-Pang Hsieh; Jang-Yang Chang
Journal:  Expert Opin Investig Drugs       Date:  2009-04       Impact factor: 6.206
  10 in total
  5 in total

1.  Development of o-chlorophenyl substituted pyrimidines as exceptionally potent aurora kinase inhibitors.

Authors:  Matthew P Martin; Yunting Luo; Roberta Pireddu; Hua Yang; Harsukh Gevariya; Harshani R Lawrence; Sevil Ozcan; Jin-Yi Zhu; Robert Kendig; Mercedes Rodriguez; Roy Elias; Jin Q Cheng; Saïd M Sebti; Ernst Schonbrunn; Nicholas J Lawrence
Journal:  J Med Chem       Date:  2012-08-30       Impact factor: 7.446

2.  A bulky biaryl phosphine ligand allows for palladium-catalyzed amidation of five-membered heterocycles as electrophiles.

Authors:  Mingjuan Su; Stephen L Buchwald
Journal:  Angew Chem Int Ed Engl       Date:  2012-03-30       Impact factor: 15.336

3.  A simple and rapid UHPLC-MS/MS method for the quantitation of the dual aurora kinase A/B inhibitor SCH-1473759 in murine plasma.

Authors:  Marco A Ferraz Nogueira Filho; Cody J Peer; Jeffers Nguyen; Amy McCalla; Lee Helman; William D Figg
Journal:  J Pharm Biomed Anal       Date:  2016-10-05       Impact factor: 3.935

4.  The discovery of aurora kinase inhibitor by multi-docking-based virtual screening.

Authors:  Jun-Tae Kim; Seo Hee Jung; Sun Young Kang; Chung-Kyu Ryu; Nam Sook Kang
Journal:  Int J Mol Sci       Date:  2014-11-06       Impact factor: 5.923

Review 5.  Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy.

Authors:  Ruijuan Du; Chuntian Huang; Kangdong Liu; Xiang Li; Zigang Dong
Journal:  Mol Cancer       Date:  2021-01-15       Impact factor: 27.401
  5 in total

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