PLK1 inhibitor | BI-2536

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Target protein: 
PLK1
Probe Name: 
BI-2536
MOLECULAR WEIGHT [DA]: 
521.7
In stock: 
2300

Chemical structure

2D Structure PLK1

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)

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

Download selectivity data: 

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

References

  1. 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

  2. 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

  3. Targeting polo-like kinase 1 for cancer therapy

    Strebhardt K., Ullrich A.

    Nature Reviews Cancer 6 2006, 17, 321-330

  4. Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology

    Schöffski P.
    Oncologist 2009, 14, 559-70

  5. Polo on the Rise-from Mitotic Entry to Cytokinesis with PLK1

    Petronczki M., Lénárt P., Peters J. M.

    Dev Cell, 2009, 14, 646-59

  6. 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

  7. 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.

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