PLK1 inhibitor | BI-2536
Highlights
BI-2536 is a potent and selective Polo-like kinase 1 (PLK1) inhibitor (IC50 = 0.8 nM). Its activity has been demonstrated in a large variety of human tumor cell lines, as well as in mouse xenograft models (i.v. administration). This compound is suitable for both in vitro and in vivo studies. BI-2536 was the first PLK1 inhibitor to enter clinical trials.
Background information
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 (X-ray structure solved at BI).
In vitro activity
BI-2536 shows IC50 values in a large panel of human tumor cell lines (carcinomas, sarcomas, melanomas and tumors derived from haemotological 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 (EC50) [nM] | 12 |
In vitro DMPK and CMC 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: IC50 = 3.5 nM
PLK3: IC50 = 9 nM
High overall kinase selectivity:
> 1000-fold (panel of 63 protein kinases, supplemental data)1
| SELECTIVITY DATA AVILABLE | BI-2536 |
SafetyScreen44™ with kind support of  | Yes |
| Invitrogen® | No |
| DiscoverX® | Yes6 |
| Dundee | Yes |
Download selectivity data:
BI-2536_selectivityData_0.xlsx
Co-crystal structure of the BI probe compound and the target protein
X-ray co-crystal structure available: PDB-code: 2RKU
Reference molecule(s)
- 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
BI-2536, 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
How to cite opnMe?
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BI-2536 was kindly provided by Boehringer Ingelheim via its open innovation platform opnMe, available at https://opnme.com.
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