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MLN8054 

MLN8054  is an aurora kinase inhibitor MLN8054, which is an orally bioavailable, highly selective small molecule inhibitor of the serine/threonine protein kinase Aurora A kinase with potential antineoplastic activity. Auora kinase inhibitor MLN8054 binds to and inhibits Aurora kinase A, resulting in disruption of the assembly of the mitotic spindle apparatus, disruption of chromosome segregration, and inhibition of cell proliferation. Aurora A localizes in mitosis to the spindle poles and to spindle microtubules and is thought to regulate spindle assembly. Aberrant expression of Aurora kinases occurs in a wide variety of cancers, including colon and breast cancers. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:   Millennium Pharmaceuticals Inc.

Phase I trials using MLN8054:  Patients with advanced solid tumors received MLN8054 orally for 7 consecutive days in escalating dose cohorts, with skin and tumor biopsies obtained before and after dosing.  Several patients in the highest dose cohorts showed marked increases in the skin mitotic index after dosing. Although some tumors exhibited increases in mitotic cells after dosing, others displayed decreases, a variable outcome consistent with dual mechanisms of mitotic arrest and mitotic slippage induced by antimitotics in tumors. Several patients, primarily in the highest dose cohorts, had marked decreases in the percentage of mitotic cells with aligned chromosomes and bipolar spindles after dosing. Evidence existed for an exposure-effect relationship for mitotic cells with defects in chromosome alignment and spindle bipolarity that indicated a biologically active dose range. Outcomes of pharmacodynamic assays from skin and tumor biopsies were concordant in several patients. Together, these new pharmacodynamic assays provide evidence for Aurora A inhibition by MLN8054 in patient skin and tumor tissues. (source: Cancer Res. 2011 Feb 1;71(3):675-85.)

MLN8054 sensitizes androgen-resistant prostate cancer to radiation.  Researcers at Vanderbilt University recently reported that MLN8054 showed radiation sensitization in androgen-insensitive prostate cancer in vitro and in vivo. This warrants the clinical development of MLN8054 with radiation for prostate cancer patients. In vitro inhibition of Aurora-A by MLN8054 sensitized prostate cancer cells, as determined by dose enhancement ratios in clonogenic assays. These effects were associated with sustained DNA double-strand breaks, as evidenced by increased immunofluorescence for γ-H2AX and significant G2/M accumulation and polyploidy. In vivo, the addition of MLN8054 (30 mg/kg/day) to radiation in mouse prostate cancer xenografts (PC3 cells) significantly increased tumor growth delay and apoptosis (caspase-3 staining), with reduction in cell proliferation (Ki67 staining) and vascular density (von Willebrand factor staining). (source: Int J Radiat Oncol Biol Phys. 2011 Jul 15;80(4):1189-97.)

1: Kwiatkowski N, Deng X, Wang J, Tan L, Villa F, Santaguida S, Huang HC, Mitchison T, Musacchio A, Gray N. Selective Aurora Kinase Inhibitors Identified Using a Taxol-Induced Checkpoint Sensitivity Screen. ACS Chem Biol. 2011 Oct 21. [Epub ahead of print] PubMed PMID: 21992004.

2: Emery A, Sorrell DA, Lawrence S, Easthope E, Stockdale M, Jones DO, Zheleva D, Scaerou F, Glover DM. A novel cell-based, high-content assay for phosphorylation of Lats2 by Aurora A. J Biomol Screen. 2011 Sep;16(8):925-31. Epub 2011 Jul 25. PubMed PMID: 21788394.

3: Moretti L, Niermann K, Schleicher S, Giacalone NJ, Varki V, Kim KW, Kopsombut P, Jung DK, Lu B. MLN8054, a small molecule inhibitor of aurora kinase a, sensitizes androgen-resistant prostate cancer to radiation. Int J Radiat Oncol Biol Phys. 2011 Jul 15;80(4):1189-97. Epub 2011 Apr 20. PubMed PMID: 21514073.

4: Wunderlich A, Fischer M, Schlosshauer T, Ramaswamy A, Greene BH, Brendel C, Doll D, Bartsch D, Hoffmann S. Evaluation of Aurora kinase inhibition as a new therapeutic strategy in anaplastic and poorly differentiated follicular thyroid cancer. Cancer Sci. 2011 Apr;102(4):762-8. doi: 10.1111/j.1349-7006.2011.01853.x. Epub 2011 Feb 17. PubMed PMID: 21214672.

5: Chakravarty A, Shinde V, Tabernero J, Cervantes A, Cohen RB, Dees EC, Burris H, Infante JR, Macarulla T, Elez E, Andreu J, Rodriguez-Braun E, Rosello S, von Mehren M, Meropol NJ, Langer CJ, ONeil B, Bowman D, Zhang M, Danaee H, Faron-Yowe L, Gray G, Liu H, Pappas J, Silverman L, Simpson C, Stringer B, Tirrell S, Veiby OP, Venkatakrishnan K, Galvin K, Manfredi M, Ecsedy JA. Phase I assessment of new mechanism-based pharmacodynamic biomarkers for MLN8054, a small-molecule inhibitor of Aurora A kinase. Cancer Res. 2011 Feb 1;71(3):675-85. Epub 2010 Dec 10. PubMed PMID: 21148750.

6: Macarulla T, Cervantes A, Elez E, Rodríguez-Braun E, Baselga J, Roselló S, Sala G, Blasco I, Danaee H, Lee Y, Ecsedy J, Shinde V, Chakravarty A, Bowman D, Liu H, Eton O, Fingert H, Tabernero J. Phase I study of the selective Aurora A kinase inhibitor MLN8054 in patients with advanced solid tumors: safety, pharmacokinetics, and pharmacodynamics. Mol Cancer Ther. 2010 Oct;9(10):2844-52. Epub 2010 Aug 19. PubMed PMID: 20724522.

7: Dees EC, Infante JR, Cohen RB, O'Neil BH, Jones S, von Mehren M, Danaee H, Lee Y, Ecsedy J, Manfredi M, Galvin K, Stringer B, Liu H, Eton O, Fingert H, Burris H. Phase 1 study of MLN8054, a selective inhibitor of Aurora A kinase in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2011 Apr;67(4):945-54. Epub 2010 Jul 7. PubMed PMID: 20607239; PubMed Central PMCID: PMC3026871.

8: Sloane DA, Trikic MZ, Chu ML, Lamers MB, Mason CS, Mueller I, Savory WJ, Williams DH, Eyers PA. Drug-resistant aurora A mutants for cellular target validation of the small molecule kinase inhibitors MLN8054 and MLN8237. ACS Chem Biol. 2010 Jun 18;5(6):563-76. PubMed PMID: 20426425.

9: Huck JJ, Zhang M, McDonald A, Bowman D, Hoar KM, Stringer B, Ecsedy J, Manfredi MG, Hyer ML. MLN8054, an inhibitor of Aurora A kinase, induces senescence in human tumor cells both in vitro and in vivo. Mol Cancer Res. 2010 Mar;8(3):373-84. Epub 2010 Mar 2. PubMed PMID: 20197380.

10: Dodson CA, Kosmopoulou M, Richards MW, Atrash B, Bavetsias V, Blagg J, Bayliss R. Crystal structure of an Aurora-A mutant that mimics Aurora-B bound to MLN8054: insights into selectivity and drug design. Biochem J. 2010 Mar 15;427(1):19-28. Erratum in: Biochem J. 2010;427(3):551. PubMed PMID: 20067443.

11: Shang X, Burlingame SM, Okcu MF, Ge N, Russell HV, Egler RA, David RD, Vasudevan SA, Yang J, Nuchtern JG. Aurora A is a negative prognostic factor and a new therapeutic target in human neuroblastoma. Mol Cancer Ther. 2009 Aug;8(8):2461-9. Epub 2009 Aug 11. PubMed PMID: 19671766.

12: Kaestner P, Stolz A, Bastians H. Determinants for the efficiency of anticancer drugs targeting either Aurora-A or Aurora-B kinases in human colon carcinoma cells. Mol Cancer Ther. 2009 Jul;8(7):2046-56. Epub 2009 Jul 7. PubMed PMID: 19584233.

13: Scutt PJ, Chu ML, Sloane DA, Cherry M, Bignell CR, Williams DH, Eyers PA. Discovery and exploitation of inhibitor-resistant aurora and polo kinase mutants for the analysis of mitotic networks. J Biol Chem. 2009 Jun 5;284(23):15880-93. Epub 2009 Apr 9. PubMed PMID: 19359241; PubMed Central PMCID: PMC2708884.

14: Wysong DR, Chakravarty A, Hoar K, Ecsedy JA. The inhibition of Aurora A abrogates the mitotic delay induced by microtubule perturbing agents. Cell Cycle. 2009 Mar 15;8(6):876-88. Epub 2009 Mar 21. PubMed PMID: 19221504.

15: Li J, Anderson MG, Tucker LA, Shen Y, Glaser KB, Shah OJ. Inhibition of Aurora B kinase sensitizes a subset of human glioma cells to TRAIL concomitant with induction of TRAIL-R2. Cell Death Differ. 2009 Mar;16(3):498-511. Epub 2008 Dec 12. PubMed PMID: 19079141.

16: Dar AA, Belkhiri A, Ecsedy J, Zaika A, El-Rifai W. Aurora kinase A inhibition leads to p73-dependent apoptosis in p53-deficient cancer cells. Cancer Res. 2008 Nov 1;68(21):8998-9004. PubMed PMID: 18974145; PubMed Central PMCID: PMC2587495.

17: LeRoy PJ, Hunter JJ, Hoar KM, Burke KE, Shinde V, Ruan J, Bowman D, Galvin K, Ecsedy JA. Localization of human TACC3 to mitotic spindles is mediated by phosphorylation on Ser558 by Aurora A: a novel pharmacodynamic method for measuring Aurora A activity. Cancer Res. 2007 Jun 1;67(11):5362-70. PubMed PMID: 17545617.

18: Hoar K, Chakravarty A, Rabino C, Wysong D, Bowman D, Roy N, Ecsedy JA. MLN8054, a small-molecule inhibitor of Aurora A, causes spindle pole and chromosome congression defects leading to aneuploidy. Mol Cell Biol. 2007 Jun;27(12):4513-25. Epub 2007 Apr 16. PubMed PMID: 17438137; PubMed Central PMCID: PMC1900054.

19: Manfredi MG, Ecsedy JA, Meetze KA, Balani SK, Burenkova O, Chen W, Galvin KM, Hoar KM, Huck JJ, LeRoy PJ, Ray ET, Sells TB, Stringer B, Stroud SG, Vos TJ, Weatherhead GS, Wysong DR, Zhang M, Bolen JB, Claiborne CF. Antitumor activity of MLN8054, an orally active small-molecule inhibitor of Aurora A kinase. Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4106-11. Epub 2007 Feb 23. PubMed PMID: 17360485; PubMed Central PMCID: PMC1820716.