Aurora B inhibitor | BI 831266
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Highlights
The serine-threonine kinase Aurora B belongs to the highly conserved Aurora family. As a chromosomal passenger protein Aurora B is involved in chromosome segregation, spindle-checkpoint, and cytokinesis.1 BI 831266 demonstrates good Aurora B binding potency within the nanomolar range and inhibits cellular proliferation in vitro with an IC50 of around 10 nM. The BI 831266 Aurora B inhibitor with its DMPK profile showed tumor growth inhibition in in vivo xenograft models. Together with the also available structurally similar compound BI-1282, which can be used as negative control due to much weaker potency, BI 831266 can serve as an excellent small molecule inhibitor for testing biological hypotheses in vitro and in vivo.
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Target information
The family of 3 nuclear serine-threonine kinases Aurora A, B and C play important roles in maintaining genetic stability and fidelity of mitosis of cells.
The Aurora kinases share a highly conserved catalytic domain but different subcellular localizations. Aurora kinases contain mainly two domains: 1) NH2-terminal regulatory domain, 2) COOH-terminal catalytic domain. The three auroras A, B, and C share great homology in the catalytic domain. Phosphorylation at threonine within the activation loop is necessary for kinase activity.2
Aurora B regulates chromosomal orientation, chromosome condensation, spindle assembly, and cytokinesis. It plays a direct role in histone H3 phosphorylation.
The overexpression of Aurora B has been observed in several tumor types, and has been linked with a poor prognosis of cancer patients.3
BI 831266 bound to Aurora B, as observed by X-ray (structure solved at Boehringer Ingelheim)
In vitro Activity
BI 831266 is a potent Aurora B inhibitor with an IC50 of 42 nM.
In vitro activity table
|
Probe name / Negative control |
BI 831266 |
BI-1282 |
|
MW [Da] |
528.1 |
505.6 |
|
Aurora B binding (IC50) [nM] |
42 |
>4000 |
|
Aurora B binding Invitrogen® Panel (IC50) [nM] |
25 |
- |
|
Histone H3 phosphorylation modulation as biomarker (IC50) [nM] |
51 |
n.d. |
|
H460 polyploide phenotype > 50% [nM] |
14 |
n.d. |
|
H460 tumor cell proliferation inhibition (IC50) [nM] |
11 |
n.d. |
In vitro DMPK parameters
|
Probe name / Negative control |
BI 831266 |
BI-1282 |
|
Solubility @ pH 7.4 [µg/ml] |
875 |
n.d. |
|
CACO permeability @ pH 7.4 [*10-6 cm/s] |
6.1 |
n.d. |
|
CACO efflux ratio |
6.0 |
n.d. |
|
Human hepatocyte clearance [% QH] |
12 |
n.d. |
|
Plasma protein binding human [%] |
48 |
n.d. |
In vivo DMPK parameters
|
Probe name |
BI 831266 |
||
|
Species |
mouse |
rat |
dog |
|
Dose i.v./p.o. [mg/kg] |
10 / 10 |
4 / 10 |
0.5 / 2 |
|
CL [% QH] |
71 |
45 |
19 |
|
Mean residence time after iv dose (l/kg) |
0.6 |
1.4 |
1.0 |
|
F [%] |
34 |
20 |
9 |
|
Vss [l/kg] |
2.6 |
3.6 |
1.1 |
Negative control
BI-1282 (negative control)
The diaminopyrimidine BI-1282 with the N-methyl group to block kinase hinge- binding can be used as an in vitro negative control.
Selectivity
Extensive external screens available (also see supplementary data):
Invitrogen® panel: 47 kinases screened @ 1 µM
Selected IC50s measured @ Invitrogen®:
AURKB IC50 = 25 nM; AURKC IC50 = 37 nM; RET IC50 = 169 nM; EPHA2 IC50 = 181 nM; STK6 IC50 = 183 nM; AMPK A1B1G1 IC50 = 2.95 µM; AMPK A2B1G1 IC50 = 3.88 µM
Dundee panel: 87 kinases screened @ 1 and 3 µM
DiscoverX® panel: 468 kinases screened @ 1 µM
Panlabs® External screen covering 68 targets @ 10 µM
Selectivity data available
|
Probe name |
BI 831266 |
|
Cerep® |
No |
|
Eurofins-Panlabs® |
Yes |
|
Invitrogen® |
Yes |
|
DiscoverX® |
Yes |
|
Dundee |
Yes |
Co-crystal structure of the BI probe compound and the target protein
The Xray crystal structure of Aurora B/INCENP in complex with the -CF3 analog of the probe (BI 811283) is available (PDB code: 5K3Y)4
reference molecules
AMG-900, AZD1152, AT9283, VX-680(MK-0457), PHA-680632, PHA-739358, CYC-116
Summary
BI 831266 is a potent and selective Aurora B inhibitor that inhibits cell proliferation and could be used as tool compound testing biological hypotheses.
Supplementary data
References
Aurora kinases: novel therapy targets in cancers
Anqun Tang, Keyu Gao, Laili Chu, Rui Zhang, Jing Yang and Junnian Zheng
Oncotarget 2017;Vol. 8,(No. 14):23937-23954.
Aurora Kinase inhibitors: Current Status and Outlook
Vassilios Bavetsias and Spiros Linardopoulos
Front. Oncol. 2015;5:278,1-10.
Aurora Kinases and Potential Medical Applications of Aurora Kinase Inhibitors: A Review
Paschalis Gavriilidisa, Alexandros Giakoustidis, Dimitrios Giakoustidis
J Clin Med Res. 2015;7(10):742-751.
Pharmacological Profile of BI 847325, an Orally Bioavailable, ATP-Competitive Inhibitor of MEK and Aurora Kinases
Sini P, Gurtler U, Zahn SK, Baumann C, Rudolph D, Baumgartinger R, Strauss E, Haslinger C, Tontsch-Grunt U, Waizenegger IC, Solca F, Bader G, Zoephel A, Treu M, Reiser U, Garin-Chesa P, Boehmelt G, Kraut N, Quant J, Adolf GR
Mol. Cancer Ther. 2016;15:2388-2398.
