PLK1 inhibitor | BI-2536
ReviewsChemical structure
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).
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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 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 |
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 et al.
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. et al.
Current Biology 17, 1–12, February 19, 2007
Targeting polo-like kinase 1 for cancer therapy
Strebhardt, K & Ullrich, A.
Nature Reviews Cancer 6, 321-330 (April 2006)
Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology
Schöffski P.
Oncologist 2009 Jun;14(6):559-70Polo on the Rise-from Mitotic Entry to Cytokinesis with PLK1
Petronczki M et al.
Dev Cell, 2009 May;14(5):646-59
Comprehensive analysis of kinase inhibitor selectivity
Davis, M. I. et al.
Nature Biotechnology Volume: 29, Pages:1046–1051(2011)
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.
