BI 811283 explained

Legal Status:Investigational
Iupac Name:4-((4-(((1R,2S)-2-(isopropylcarbamoyl)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide
Cas Number:1802182-21-3
C:28
H:38
F:3
N:7
O:2
Stdinchi:1S/C28H38F3N7O2/c1-17(2)33-25(39)21-6-5-7-23(21)35-24-22(28(29,30)31)16-32-27(36-24)34-19-10-8-18(9-11-19)26(40)38(4)20-12-14-37(3)15-13-20/h8-11,16-17,20-21,23H,5-7,12-15H2,1-4H3,(H,33,39)(H2,32,34,35,36)/t21-,23+/m0/s1
Smiles:FC(F)(F)C(C=N1)=C(N[C@@]2(CCC[C@@]2(C(NC(C)C)=O)[H])[H])N=C1NC3=CC=C(C(N(C)C4CCN(C)CC4)=O)C=C3

BI 811283 is a small molecule inhibitor of the Aurora B kinase protein being developed by Boehringer Ingelheim for use as an anti-cancer agent. BI 811283 is currently in the early stages of clinical development and is undergoing first in human trials in patients with solid tumors and acute myeloid leukemia.

Mechanism of action

BI 811283 is a small molecule drug that selectively binds to the ATP binding pocket of Aurora B kinase, inhibiting its function in cell division.[1] The Aurora B kinase protein (also known as STK12) is one of a family of proteins that plays an essential role in the alignment, movement and separation of chromosomes during cell division. Aurora B kinase is produced in all dividing cells in normal tissue however; the levels of Aurora B kinase are abnormally raised in many types of cancer.[2] [3] [4] [5] [6] [7] [8] [9] [10] Abnormally elevated levels of Aurora B kinase, cause unequal chromosomal separation during cell division, resulting in the formation of cells with abnormal numbers of chromosomes, which are both a cause and driver of cancer.

Inhibition of Aurora B kinase by BI 811283 in cancer cells leads to the formation of cells with severely abnormal numbers of chromosomes (polyploid). Counterintuitively, inhibition of Aurora B kinase by BI 811283 actually causes the polyploid cells formed to continue dividing however, because these cells have severe chromosomal abnormalities, they eventually stop dividing or undergo cell death.

Clinical Uses

BI 811283 is currently undergoing investigation in phase 1 and 2 trials and has yet to be licensed by the FDA. BI 811283 may be active in a range of malignancies that are known to have raised levels of Aurora B kinase including; non-small cell lung, brain, head and neck, colorectal and ovarian cancer, where it is associated with worse treatment outcome and poorer overall survival.

Further phase 1 and 2 trials are underway investigating the use of BI 811283 in patients with different types of advanced solid tumours and Acute Myeloid Leukaemia.

Adverse Effects

Traditional anti-cancer agents that block cell division commonly cause severe adverse effects. BI 811283 has been developed to selectively target dividing cells, therefore reducing the severity of adverse effects experience by patients. The most common and severe side effect experienced with BI 811283 is a reduction in the number of white blood cells (leucopenia and neutropenia) which occurs in between 17-42% of patients and can increase the risk of infections and fever.[11] [12]

Studies

Pre-clinical studies have demonstrated that BI 811283 selectively binds to and inhibits the Aurora B kinase protein leading to inhibition of growth and senescence in lung cancer cells in vitro. Furthermore, BI 811283 also inhibits the growth of pancreatic, colorectal and non-small cell lung cancer cells in vivo leading to tumour shrinkage.

First in man clinical trials have demonstrated that BI 811283 is safe and stable in the blood stream. Two early clinical trials have reported that BI 811283 has anti-tumour activity, preventing the progression of cancer in between 29-33% of patients with advanced solid tumours.[13]

Notes and References

  1. 28 . 15 Suppl e13632 . e13632 . Gürtler U, Tontsch-Grunt U, Zahn SK, Quant J, Adolf GR, Solca F . Effect of BI 811283, a novel inhibitor of Aurora B kinase, on tumor senescence and apoptosis. . J. Clin. Oncol. . 2010 . 10.1200/jco.2010.28.15_suppl.e13632 .
  2. Araki K, Nozaki K, Ueba T, Tatsuka M, Hashimoto N . High expression of Aurora-B/Aurora and Ipll-like midbody-associated protein (AIM-1) in astrocytomas . Journal of Neuro-Oncology . 67 . 1–2 . 53–64 . 2004 . 15072448 . 10.1023/b:neon.0000021784.33421.05 . 8746338 .
  3. Chen YJ, Chen CM, Twu NF, Yen MS, Lai CR, Wu HH, Wang PH, Yuan CC . 11063495 . 6 . Overexpression of Aurora B is associated with poor prognosis in epithelial ovarian cancer patients . Virchows Archiv . 455 . 5 . 431–40 . November 2009 . 19838728 . 10.1007/s00428-009-0838-3 .
  4. Chieffi P, Cozzolino L, Kisslinger A, Libertini S, Staibano S, Mansueto G, De Rosa G, Villacci A, Vitale M, Linardopoulos S, Portella G, Tramontano D . 6 . Aurora B expression directly correlates with prostate cancer malignancy and influence prostate cell proliferation . The Prostate . 66 . 3 . 326–33 . February 2006 . 16267859 . 10.1002/pros.20345 . 37007241 .
  5. Katayama H, Brinkley WR, Sen S . 25350728 . The Aurora kinases: role in cell transformation and tumorigenesis . Cancer and Metastasis Reviews . 22 . 4 . 451–64 . December 2003 . 12884918 . 10.1023/A:1023789416385 .
  6. Pascreau G, Arlot-Bonnemains Y, Prigent C . Phosphorylation of histone and histone-like proteins by aurora kinases during mitosis . Progress in Cell Cycle Research . 5 . 369–74 . 2003 . 14593731 .
  7. Pohl A, Azuma M, Zhang W, Yang D, Ning Y, Winder T, Danenberg K, Lenz HJ . Pharmacogenetic profiling of Aurora kinase B is associated with overall survival in metastatic colorectal cancer . The Pharmacogenomics Journal . 11 . 2 . 93–9 . April 2011 . 20368716 . 10.1038/tpj.2010.18 .
  8. Qi G, Ogawa I, Kudo Y, Miyauchi M, Siriwardena BS, Shimamoto F, Tatsuka M, Takata T . 36346323 . 6 . Aurora-B expression and its correlation with cell proliferation and metastasis in oral cancer . Virchows Archiv . 450 . 3 . 297–302 . March 2007 . 17235564 . 10.1007/s00428-006-0360-9 .
  9. Sorrentino R, Libertini S, Pallante PL, Troncone G, Palombini L, Bavetsias V, Spalletti-Cernia D, Laccetti P, Linardopoulos S, Chieffi P, Fusco A, Portella G . 6 . Aurora B overexpression associates with the thyroid carcinoma undifferentiated phenotype and is required for thyroid carcinoma cell proliferation . The Journal of Clinical Endocrinology and Metabolism . 90 . 2 . 928–35 . February 2005 . 15562011 . 10.1210/jc.2004-1518 . free .
  10. Zeng WF, Navaratne K, Prayson RA, Weil RJ . Aurora B expression correlates with aggressive behaviour in glioblastoma multiforme . Journal of Clinical Pathology . 60 . 2 . 218–21 . February 2007 . 17264249 . 1860618 . 10.1136/jcp.2006.036806 .
  11. 28 . Suppl e13065 . e13065 . cheulen ME, Mross KB, Richly H, Nokay B, Frost A, Scharr D, Lee K, Saunders O, Hilbert J, Fietz O . A phase I dose-escalation study of BI 811283, an Aurora B inhibitor, administered days 1 and 15, every four weeks in patients with advanced solid tumors . J. Clin. Oncol. . 2010 . 10.1200/jco.2010.28.15_suppl.e13065 .
  12. 28 . 15 Suppl. a3011 . 3011 . Mross KB, Scheulen ME, Frost A, Scharr D, Richly H, Nokay B, Lee K, Hilbert J, Fleischer F, Fietz O . A phase I dose-escalation study of BI 811283, an Aurora B inhibitor, administered every three weeks in patients with advanced solid tumors . J. Clin. Oncol. . 2010 . 10.1200/jco.2010.28.15_suppl.3011 .
  13. 51 . 262 . Gürtler U, Tontsch-Grunt U, Zahn SK, Quant J, Adolf GR, Solca F . BI 811283, a potent inhibitor of the mitotic kinase Aurora B, shows dose-and schedule-dependent efficacy in human cancer xenograft models . Proc. Am. Assoc. Cancer. Res. . 2010 .

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