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MedKoo product information:

 AZD-1152HQPA

AZD-1152 is a novel acetanilide-substituted pyrazole-aminoquinazoline prodrug that is converted rapidly to the active drug AZD-1152 hydroxy-QPA (AZD1152-HQPA) in human plasma. AZD1152-HQPA is a specific inhibitor of the enzymatic activity of Aurora kinase, with selectivity for Aurora B (IC50 of 0.37 nM versus 1368 nM for Aurora B and A kinases, respectively); the inhibitor had even less activity against a panel of greater than 50 other serine-threonine and tyrosine kinases including FLT3, JAK2, and Abl. Preliminary studies showed that AZD-1152 was active against a variety of solid tumors including colon, breast, and lung cancers.

Current developer:  AstraZeneca, Inc.

AZD1152-HQPA is a highly potent and selective Aurora B inhibitor with a Ki of 0.36 nM. AZD1152-HQPA inhibits Aurora A with a Ki of 1.37 nM. AZD1152 is converted rapidly to the active AZD1152-HQPA (Barasertib) in plasma. AZD1152-HQPA has a high specificity versus a panel of 50 other kinases. Consistent with inhibition of Aurora B kinase, addition of AZD1152-HQPA to tumor cells in vitro induces chromosome misalignment, prevents cell division, and consequently reduces cell viability and induces apoptosis.

1. Gully CP, Zhang F, Chen J, Yeung JA, Velazquez-Torres G, Wang E, Yeung SC, Lee MH. Antineoplastic effects of an Aurora B kinase inhibitor in breast cancer. Mol  Cancer. 2010 Feb 22;9:42. PubMed PMID: 20175926; PubMed Central PMCID: PMC2839967.

2: Ikezoe T, Yang J, Nishioka C, Yokoyama A. p53 is critical for the Aurora B kinase inhibitor-mediated apoptosis in acute myelogenous leukemia cells. Int J Hematol. 2010 Jan;91(1):69-77. Epub 2009 Dec 16. PubMed PMID: 20013323.

3: Ikezoe T, Takeuchi T, Yang J, Adachi Y, Nishioka C, Furihata M, Koeffler HP, Yokoyama A. Analysis of Aurora B kinase in non-Hodgkin lymphoma. Lab Invest. 2009 Dec;89(12):1364-73. Epub 2009 Oct 12. PubMed PMID: 19823168.

4: Tao Y, Leteur C, Calderaro J, Girdler F, Zhang P, Frascogna V, Varna M, Opolon P, Castedo M, Bourhis J, Kroemer G, Deutsch E. The aurora B kinase inhibitor AZD1152 sensitizes cancer cells to fractionated irradiation and induces mitotic catastrophe. Cell Cycle. 2009 Oct 1;8(19):3172-81. Epub 2009 Oct 4. PubMed PMID:  19755861.

5: Pluim D, Beijnen JH, Schellens JH, van Tellingen O. Simultaneous determination of AZD1152 (prodrug) and AZD1152-hydroxyquinazoline pyrazol anilide by reversed phase liquid chromatography. J Chromatogr B Analyt Technol Biomed Life Sci. 2009  Nov 1;877(29):3549-55. Epub 2009 Aug 28. PubMed PMID: 19744901.

6: Lorenzo C, Liao Q, Hardwicke MA, Ducommun B. Pharmacological inhibition of aurora-A but not aurora-B impairs interphase microtubule dynamics. Cell Cycle. 2009 Jun 1;8(11):1733-7. Epub 2009 Jun 2. PubMed PMID: 19395863.

7: Oke A, Pearce D, Wilkinson RW, Crafter C, Odedra R, Cavenagh J, Fitzgibbon J,  Lister AT, Joel S, Bonnet D. AZD1152 rapidly and negatively affects the growth and survival of human acute myeloid leukemia cells in vitro and in vivo. Cancer Res. 2009 May 15;69(10):4150-8. Epub 2009 Apr 14. PubMed PMID: 19366807; PubMed Central PMCID: PMC2684546.

8: Pinel S, Barbault-Foucher S, Lott-Desroches MC, Astier A. [Inhibitors of aurora kinases]. Ann Pharm Fr. 2009 Mar;67(2):69-77. Epub 2009 Feb 23. Review. French. PubMed PMID: 19298889.

9: Anderson K, Lai Z, McDonald OB, Stuart JD, Nartey EN, Hardwicke MA, Newlander  K, Dhanak D, Adams J, Patrick D, Copeland RA, Tummino PJ, Yang J. Biochemical characterization of GSK1070916, a potent and selective inhibitor of Aurora B and  Aurora C kinases with an extremely long residence time1. Biochem J. 2009 May 13;420(2):259-65. PubMed PMID: 19284385.

10: Nair JS, de Stanchina E, Schwartz GK. The topoisomerase I poison CPT-11 enhances the effect of the aurora B kinase inhibitor AZD1152 both in vitro and in vivo. Clin Cancer Res. 2009 Mar 15;15(6):2022-30. Epub 2009 Mar 10. PubMed PMID:  19276280.

11: Nair JS, Ho AL, Tse AN, Coward J, Cheema H, Ambrosini G, Keen N, Schwartz GK. Aurora B kinase regulates the postmitotic endoreduplication checkpoint via phosphorylation of the retinoblastoma protein at serine 780. Mol Biol Cell. 2009  Apr;20(8):2218-28. Epub 2009 Feb 18. PubMed PMID: 19225156; PubMed Central PMCID: PMC2669029.

12: Guo J, Anderson MG, Tapang P, Palma JP, Rodriguez LE, Niquette A, Li J, Bouska JJ, Wang G, Semizarov D, Albert DH, Donawho CK, Glaser KB, Shah OJ. Identification of genes that confer tumor cell resistance to the aurora B kinase  inhibitor, AZD1152. Pharmacogenomics J. 2009 Apr;9(2):90-102. Epub 2009 Feb 3. PubMed PMID: 19188929.

13: Walsby E, Walsh V, Pepper C, Burnett A, Mills K. Effects of the aurora kinase inhibitors AZD1152-HQPA and ZM447439 on growth arrest and polyploidy in acute myeloid leukemia cell lines and primary blasts. Haematologica. 2008 May;93(5):662-9. Epub 2008 Mar 26. PubMed PMID: 18367484.

14: Cummings J, Hodgkinson C, Odedra R, Sini P, Heaton SP, Mundt KE, Ward TH, Wilkinson RW, Growcott J, Hughes A, Dive C. Preclinical evaluation of M30 and M65 ELISAs as biomarkers of drug induced tumor cell death and antitumor activity. Mol Cancer Ther. 2008 Mar;7(3):455-63. PubMed PMID: 18347133.

15: Tao Y, Zhang P, Girdler F, Frascogna V, Castedo M, Bourhis J, Kroemer G, Deutsch E. Enhancement of radiation response in p53-deficient cancer cells by the Aurora-B kinase inhibitor AZD1152. Oncogene. 2008 May 22;27(23):3244-55. Epub 2007 Dec 17. PubMed PMID: 18084327.

16: Evans RP, Naber C, Steffler T, Checkland T, Maxwell CA, Keats JJ, Belch AR, Pilarski LM, Lai R, Reiman T. The selective Aurora B kinase inhibitor AZD1152 is  a potential new treatment for multiple myeloma. Br J Haematol. 2008 Feb;140(3):295-302. Epub 2007 Dec 10. PubMed PMID: 18076711.

17: Wilkinson RW, Odedra R, Heaton SP, Wedge SR, Keen NJ, Crafter C, Foster JR, Brady MC, Bigley A, Brown E, Byth KF, Barrass NC, Mundt KE, Foote KM, Heron NM, Jung FH, Mortlock AA, Boyle FT, Green S. AZD1152, a selective inhibitor of Aurora B kinase, inhibits human tumor xenograft growth by inducing apoptosis. Clin Cancer Res. 2007 Jun 15;13(12):3682-8. PubMed PMID: 17575233.

18: Yang J, Ikezoe T, Nishioka C, Tasaka T, Taniguchi A, Kuwayama Y, Komatsu N, Bandobashi K, Togitani K, Koeffler HP, Taguchi H, Yokoyama A. AZD1152, a novel and selective aurora B kinase inhibitor, induces growth arrest, apoptosis, and sensitization for tubulin depolymerizing agent or topoisomerase II inhibitor in human acute leukemia cells in vitro and in vivo. Blood. 2007 Sep 15;110(6):2034-40. Epub 2007 May 10. PubMed PMID: 17495131.

19: Mortlock AA, Foote KM, Heron NM, Jung FH, Pasquet G, Lohmann JJ, Warin N, Renaud F, De Savi C, Roberts NJ, Johnson T, Dousson CB, Hill GB, Perkins D, Hatter G, Wilkinson RW, Wedge SR, Heaton SP, Odedra R, Keen NJ, Crafter C, Brown  E, Thompson K, Brightwell S, Khatri L, Brady MC, Kearney S, McKillop D, Rhead S,  Parry T, Green S. Discovery, synthesis, and in vivo activity of a new class of pyrazoloquinazolines as selective inhibitors of aurora B kinase. J Med Chem. 2007 May 3;50(9):2213-24. Epub 2007 Mar 21. PubMed PMID: 17373783.  

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