PLK1 inhibitor | BI-2536

Target protein: 
PLK1
Probe Name: 
BI-2536
MOLECULAR WEIGHT [DA]: 
521.7
In stock: 
918

Chemical structure

2D Structure PLK1

Highlights

BI-2536 inhibits the PLK1 enzyme with an IC50 of 0.8 nM and is active in a large variety of human tumor cell lines in the range of EC50 = 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).

3D structure of BI-2536

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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 EC50 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 (EC50) [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: IC50 = 3.5 nM

PLK3: IC50 = 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 et al.

    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. et al.

    Current Biology 17, 1–12, February 19, 2007

  3. Targeting polo-like kinase 1 for cancer therapy

    Strebhardt, K & Ullrich, A.

    Nature Reviews Cancer 6, 321-330 (April 2006)

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

    Schöffski P.
    Oncologist 2009 Jun;14(6):559-70

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

    Petronczki M et al.

    Dev Cell, 2009 May;14(5):646-59

  6. Comprehensive analysis of kinase inhibitor selectivity

    Davis, M. I. et al.

    Nature Biotechnology Volume: 29, Pages:1046–1051(2011)

  7. BI 6727, a Polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity

    Rudolph, D. et al.

    Clin Cancer Res. 2009 May 1;15(9):3094-102.