Tuesday, July 7, 2015

Drugs in Clinical Pipeline: MLN8054

MLN8054 [4-((9-chloro-7-(2,6-difluorophenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl)amino)benzoic acid] is an orally available small-molecule reversible, ATP competitive inhibitor of recombinant Aurora A kinase (Ki = 7 nM). Additionally, MLN8054 displayed good selectivity against a panel of known kinases (IC50 Aurora A = 31 nM) [1]. The activity of MLN8054 bound to the kinase domain of Aurora A has been reported to result in an unusual activation loop conformation, which may provide a basis for selectivity over Aurora B and other kinases that cannot adopt this conformation [1,2]. Studies have showen that in cultured cells such as HCT-116 MLN8054 selectively inhibits Aurora A over Aurora B at concentrations of about 1.0 uM, whereas a 4.0 uM concentration inhibits both Aurora A and B kinases [3].

The activity of MLN8054 is as follows:

IC50 (Aurora A enzyme assay) = 31 nM; Ki = 7 nM

Common Name: MLN8054
Synonyms:  MLN8054; MLN-8054; MLN 8054
IUPAC Name: 4-((9-chloro-7-(2,6-difluorophenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl)amino)benzoic acid
CAS Number: 869363-13-3
SMILES: C1C2=CN=C(N=C2C3=C(C=C(C=C3)Cl)C(=N1)C4=C(C=CC=C4F)F)NC5=CC=C(C=C5)C(=O)O
Mechanism of Action: Kinase Inhibitor; Aurora A Kinase Inhibitor
Indication: Various Cancers; Melanomas
Development Stage: Phase I
Company: Takeda Pharma

Aurora A kinase plays an essential role in the proper assembly and function of the mitotic spindle, as its perturbation causes defects in centrosome separation, spindle pole organization, and chromosome congression.

It is suggested that Aurora A disruption leads to cell death via a mechanism that involves aneuploidy generation. However, the link between the immediate functional consequences of Aurora A inhibition and the development of aneuploidy is not clearly defined. In a reported study, authors have reproduced the sequence of events that lead to aneuploidy following Aurora A inhibition using MLN8054, a selective Aurora A small-molecule inhibitor. Human tumor cells treated with MLN8054 show a high incidence of abnormal mitotic spindles, often with unseparated centrosomes. Although these spindle defects result in mitotic delays, cells ultimately divide at a frequency near that of untreated cells. Reserachers that many of the spindles in the dividing cells are bipolar, although they lack centrosomes at one or more spindle poles. MLN8054-treated cells frequently show alignment defects during metaphase, lagging chromosomes in anaphase, and chromatin bridges during telophase. Consistent with the chromosome segregation defects, cells treated with MLN8054 develop aneuploidy over time. Taken together, these results suggest that Aurora A inhibition kills tumor cells through the development of deleterious aneuploidy [4].

1. Sells, T. B.; et. al. MLN8054 and Alisertib (MLN8237): Discovery of Selective Oral Aurora A Inhibitors. ACS Med Chem Lett 2015, 6, 630-634.
2. Dodson, C. A.; et. al. Crystal structure of an Aurora-A mutant that mimics Aurora-B bound to MLN8054: insights into selectivity and drug design. Biochem J 2010, 427(1), 19-28.
3. Huck, J. J.; et. al. MLN8054, an inhibitor of Aurora A kinase, induces senescence in human tumor cells both in vitro and in vivo. Mol Cancer Res 2010, 8(3), 373-384.
4. Hoar, K.; et. al. MLN8054, a small-molecule inhibitor of Aurora A, causes spindle pole and chromosome congression defects leading to aneuploidy. Mol Cell Biol 2007, 27(12), 4513-4525.