BI2536

Protein target name:

PLK1, PLK2, PLK3

Mechanism of action:

ATP-competitive inhibitor

Recommended Concentration for use in cells:

N/A

Probe Availability

Cayman (755038-02-9)

MedChem Express (755038-02-9)

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

Other

HUGO symbol:

PLK1 PLK2 PLK3

Entrez gene ID:

5347 10769 1263

Probe Details

Chemical Probes Portal ID:

CPP88

PubChem CID:

11364421

ChEMBL ID:

CHEMBL513909

SMILES string:

CC[C@@H]1C(=O)N(C2=CN=C(N=C2N1C3CCCC3)NC4=C(C=C(C=C4)C(=O)NC5CCN(CC5)C)OC)C

InChi Key:

XQVVPGYIWAGRNI-JOCHJYFZSA-N

PAINs evaluation:

PAINs free

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

PLK1 0.83 nM, PLK2 3.5 nM, PLK3 9 nM

Off target activity

Potency assay (off target):

>1,000-fold selective for PLK proteins over 63 additional protein kinases

In cell validation

On target activity in cells

Potency assay (cells):

In HeLa cells, BI2536 dose-dependently inhibited substrate phosphorylation, caused G2/M arrest and led to PARP p85 fragment formation, with activity saturating between 10-100 nM

Target engagement assay (cells):

Indirect: inhibition of substrate phosphorylation

Primary Reference

Reference (doi):

doi:10.1016/j.cub.2006.12.037

Reference (PMID):

17291758

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

BI-2356 has been subject to kinome profiling (doi:10.1038/nbt.1990). Although it is active against >20 kinases at 1 uM, it is potent and selective for PLK1, PLK2, and to a lesser extent PLK3 at very low nM doses. CAMKK1/2 and RPS6KA4 (Kin.Dom.2-C-terminal) would be off-targets in the ~20 nM and 12 nM range, respectively.

BI 2536 given i.v. once or twice per week is highly efficacious in diverse xenograft models with acceptable tolerability by inhibiting cell proliferation through a mitotic arrest, and subsequently induction of tumor-cell death. Administration of BI 2536 at 50 mg/kg once or twice per week significantly inhibits growth of HCT 116 xenografts with T/C of 15% and 0.3%, respectively. BI 2536 treatment twice-weekly also leads to excellent tumor-growth in BxPC-3 and A549 models with T/C of 5% and 14%, respectively.

BI 2536 blocks the activities of PLK2 and PLK3 with IC50s of 3.5 nM and 9.0 nM, respectively. In HeLa cells, BI 2536 treatment ranging from 10-100 nM leads to the blocking of the recruitment of γ-tubulin and phosphorylation of APC6 at mitotic centrosomes, inhibition of cohesin release from chromosome arms, induction of monopolar spindles, as well as a range of other mitotic processes that are known to depend on PLK1. BI 2536 treatment leads to HeLa cell arrest in G2/M, subsequently a sub-G1 DNA peak indicative of DNA breakdown and apoptosis, and accumulated cleaved PARP p85 fragments in a concentration-dependent manner. BI 2536 inhibits the growth of a panel of 32 human cancer cell lines with EC50s of 2-25 nM, while blocking the proliferation of exponentially growing hTERT-RPE1, human umbilical vein endothelial cells (HUVECs), and normal rat kidney (NRK) cells with EC50s of 12-31 nM. PLK1 inhibition by BI 2536 reduces the growth and viability of anaplastic thyroid carcinoma (ATC) cells such as CAL62, OCUT-1, SW1736, 8505C, and ACT-1 with EC50 values of 1.4-5.6 nM.

BI2536 is a potent inhibitor of the PLK kinase family (PLK1/2/3 IC50 0.83/3.5/9.0 nM). Its selectivity was excellent in a protein kinase panel of modest size (63 other kinases). PLK4 was not a member of that panel. BI2536 is cell-permeable, causing HeLa cell-cycle block in G2 or mitosis at 10-50 nM and inhibiting a range of other cancer cell proliferation at 1-100 nM EC50. It was effective in a mouse xenograft model intravenously dosed (40-50 mg/kg weekly or bi-weekly). This compound is not a pure PLK chemical probe; it is also a potent inhibitor of the BET family bromodomains (BRD4-BD1 IC50 25 nM by AlphaScreen, Kd 37 nM by ITC, IC50 100 nM vs BRD4 in a FRAP cellular assay) and has a polypharmacological profile (doi:10.1021/cb500072z, doi:10.1038/nchembio.1471) For that reason, I would not choose this compound as a selective probe for the PLK family.

BI2536

Probe Availability

Probe Information

Target Details

Probe Details

In vitro validation

In cell validation

Primary Reference

Supporting Organizations

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BI2536

Probe Availability

Probe Information

Target Details

Probe Details

In vitro validation

In cell validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?