PLK1 inhibitor | BI-2536
Write a review / see user reviewsChemical structure
Highlights
BI-2536 inhibits the PLK1 enzyme with an 50 of 0.8 nM and is active in a large variety of human tumor cell lines in the range of 50 = 2-25 nM. In vivo, BI-2536 is efficacious in mouse xenograft models in the range of 30-60 mg/kg (once or twice weekly i.v. administration).
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Target information
Polo-like kinase 1 (PLK1) is a key regulator of cell division in eukaryotic cells. PLK1 contributes to the activation of the cyclin B1/CDK1 complex and is involved in centrosome maturation and bipolar spindle formation at the onset of mitosis. Moreover, PLK1 controls mitotic exit by regulating the anaphase-promoting complex, and it is also involved in the temporal and spatial coordination of cytokinesis.
BI-2536 bound to PLK1 (Xray structure solved at BI)
In vitro Activity
BI-2536 shows 50 values in a large panel of human tumor cell lines (carcinomas, sarcomas, melanomas and tumors derived from hematological malignancies) in the range of 2 to 25 nM.1
|
Probe name |
BI-2536 |
|
MW [Da] |
521.7 |
|
PLK1 (IC50) [nM] |
0.83 |
|
NCI-H460 (50) [nM] |
12 |
In vitro DMPK parameters
|
Probe name |
BI-2536 |
||
|
Solubility @ pH 5, McIlvaine buffer [µg/ml] |
320 |
||
|
CACO permeability @ pH 7.4 [*10-6 cm/s] |
16 |
||
|
CACO efflux ratio |
3 |
||
|
Plasma protein binding human / mouse / rat [% ] |
91 |
95 |
95 |
In vivo DMPK parameters
|
BI-2536 |
Mouse |
Rat |
|
CL [% QH] |
116 |
56-200 |
|
MRT [h] |
0.8 |
0.9-2.5 |
|
Vss [L/kg] |
5.6 |
4.8-55 |
|
F [%] |
n.d |
14 |
In vivo pharmacology
BI-2536 is efficacious in mouse xenograft models in the range of 30-60 mg/kg (once or twice weekly i.v. administration).1
Selectivity
Low selectivity over closest family members:
PLK2: 50 = 3.5 nM
PLK3: 50 = 9 nM
High overall kinase selectivity:
>1000-fold (panel of 63 protein kinases, supplemental data)1
|
Probe name |
BI-2536 |
|
Cerep® |
No |
|
Eurofins-Panlabs® |
No |
|
Invitrogen® |
No |
|
DiscoverX® |
Yes6 |
|
Dundee |
Yes |
Co-crystal structure of the BI probe compound and the target protein
X-ray co-crystal structure available: PDB-code: 2RKU
reference molecules
- Volasertib (BI 6727) shows similar in vitro profile, but in vivo longer half-life7
- GSK-461364A is reported with PLK family selectivity6
Summary
BI-2536 was the first potent and selective PLK1 inhibitor which entered clinical trials. It is a suitable in vitro and in vivo tool to study PLK function.
Supplementary data
2 D structure formats available
References
a Potent and Selective Inhibitor of Polo-like Kinase 1, Inhibits Tumor Growth In Vivo
Steegmaier M., Hoffmann M., Baum A., Lénárt P., Petronczki M., Krssák M., Gürtler U., Garin-Chesa P., Lieb S., Quant J., Grauert M., Adolf G. R., Kraut N., Peters J. M., Rettig W. J.
Current Biology 2007, pp 316-322
The Small-Molecule Inhibitor BI-2536 Reveals Novel Insights into Mitotic Roles of Polo-like Kinase 1
Lénárt P., Petronczki M., Steegmaier M., Di Fiore B., Lipp J. J., Hoffmann M., Rettig W. J., Kraut N., Peters J. M.
Current Biology 17 2007, 17, 304-315
Targeting polo-like kinase 1 for cancer therapy
Strebhardt K., Ullrich A.
Nature Reviews Cancer 6 2006, 17, 321-330
Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology
Schöffski P.
Oncologist 2009, 14, 559-70Polo on the Rise-from Mitotic Entry to Cytokinesis with PLK1
Petronczki M., Lénárt P., Peters J. M.
Dev Cell, 2009, 14, 646-59
Comprehensive analysis of kinase inhibitor selectivity
Davis M. I., Hunt J. P., Herrgard S., Ciceri P., Wodicka L. M., Pallares G., Hocker M., Treiber D. K., Zarrinkar P. P.
Nature Biotechnology 2011, 29, 1046–1051
BI 6727, a Polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity
Rudolph, D. Steegmaier M., Hoffmann M., Grauert M., Baum A., Quant J., Haslinger C., Garin-Chesa P., Adolf G. R.
Clin Cancer Res. 2009 1, 15, 3094-102.
