Volasertib (BI 6727)
Molecular Weight(MW): 618.81
Volasertib (BI 6727) is a highly potent Plk1 inhibitor with IC50 of 0.87 nM in a cell-free assay. It shows 6- and 65-fold greater selectivity against Plk2 and Plk3. Phase 3.
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|Description||Volasertib (BI 6727) is a highly potent Plk1 inhibitor with IC50 of 0.87 nM in a cell-free assay. It shows 6- and 65-fold greater selectivity against Plk2 and Plk3. Phase 3.|
|Features||A high volume of distribution, indicating good tissue penetration, and a long terminal half-life.|
Like BI2536, BI6727 is an ATP-competitive kinase inhibitor from the dihydropteridinone class of compounds. In addition to Plk1, BI6727 also potently inhibits two closely related kinases Plk2 and Plk3 with IC50 of 5 nM and 56 nM, respectively. BI6727 at concentrations up to 10 μM displays no inhibitory activity against a panel of >50 other kinases. BI6727 inhibits the proliferation of multiple cell lines derived from various cancer tissues, including HCT116, NCI-H460, BRO, GRANTA-519, HL-60, THP-1, and Raji cells with EC50 of 23 nM, 21 nM, 11 nM, 15 nM, 32 nM, 36 nM, and 37 nM, respectively. BI6727 treatment (100 nM) in NCI-H460 cells induces an accumulation of mitotic cells with monopolar spindles and positive staining for histone H3 phosphoserine 10, confirming that cells are arrested early in the M phase, followed by induction of apoptosis.  Low nanomolar concentrations of BI6727 display potent inhibitory activity against neuroblastoma (NB) tumor-initiating cells (NB TIC) with EC50 of 21 nM, whereas only micromolar concentrations of BI6727 are cytotoxic for normal pediatric neural stem cells.  BI6727 induces growth arrest of Daoy and ONS-76 medulloblastoma cells similar to BI 2536. 
|In vivo||Administration of BI6727 significantly inhibits the growth of multiple human carcinoma xenografts including HCT116, NCI-H460, and taxane-resistant CXB1 colon carcinoma, accompanied by an increase in the mitotic index as well as an increase in apoptosis.  In in vivo studies, BI6727 shows better toxicity and pharmacokinetic profile compared to BI2536. |
In vitro kinase assays:Recombinant human Plk1 (residues 1-603) is expressed as NH2-terminal, GST-tagged fusion protein using a baculoviral expression system and purified by affinity chromatography using glutathione-agarose. Enzyme activity assays for Plk1 are done in the presence of serially diluted BI6727 using 20 ng of recombinant kinase and 10 μg casein from bovine milk as substrate. Kinase reactions are done in a final volume of 60 μL for 45 minutes at 30 °C [15 mM MgCl2, 25 mM MOPS (pH 7.0), 1 mM DTT, 1% DMSO, 7.5 μM ATP, 0.3 μCi γ-32P-ATP]. Reactions are terminated by the addition of 125 μL of ice-cold 5% TCA. After transferring the precipitates to MultiScreen mixed ester cellulose filter plates, plates are washed with 1% TCA and quantified radiometrically. Dose-response curves are used for calculating IC50 value.
|In vitro||DMSO||20 mg/mL warmed (32.32 mM)|
|In vivo||Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
4% DMSO+corn oil
For best results, use promptly after mixing.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
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Clinical Trial Information
|NCT Number||Recruitment||interventions||Conditions||Sponsor/Collaborators||Start Date||Phases|
|NCT02722135||Withdrawn||Drug: Volasertib||Leukemia Myeloid Acute||Boehringer Ingelheim||November 2016||Phase 1|
|NCT02721875||Terminated||Drug: Volasertib|Drug: Azacitidine||Myelodysplastic Syndromes||Boehringer Ingelheim||April 28 2016||Phase 1|
|NCT02201329||Completed||Drug: Azacitidine|Drug: Volasertib||Myelodysplastic Syndromes|Leukemia Myelomonocytic Chronic||Boehringer Ingelheim||August 2014||Phase 1|
|NCT01971476||Completed||Drug: volasertib||Leukemia|Neoplasms||Boehringer Ingelheim||October 22 2013||Phase 1|
|NCT01662505||Completed||Drug: Volasertib||Leukemia Myeloid Acute||Boehringer Ingelheim||August 2012||Phase 1|
Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.
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Frequently Asked Questions
I wonder how to reconstitute the inhibitor for in vivo studies?
Volasertib can be dissolved in 4% DMSO+Corn oil at 2mg/ml for i.p. injection in mice. For oral administration, it can be formulated in hydrochloric acid (0.1 N), and diluted with 0.9% NaCl, or suspended in 0.5% Natrosol 250 hydroxyethyl-cellulose as indicated in the publications. We also suggest the vehicle 30% PEG400/0.5% Tween80/5% propylene glycol for a suspension which we tested in house.