Volasertib (BI 6727) 755038-65-4

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Molecular Weight:

618.81 Volasertib (BI 6727) is a highly potent Plk1 inhibitor with IC50 of 0.87 nM. It shows 6- and 65-fold greater selectivity against Plk2 and Plk3. Phase 3.


Biological Activity


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.


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.


Protocol(Only for Reference)


Kinase Assay: [1]

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.

Cell Assay: [1]

Cell lines	HCT116, NCI-H460, BRO, GRANTA-519, HL-60, THP-1, and Raji
Concentrations	Dissolved in DMSO, final concentrations ~1 μM
Incubation Time	24, 48, and 72 hours
Method	Cell proliferation assays are done by incubating cells in the presence of various concentrations of BI6727 for 24, 48, and 72 hours and cell growth is assessed by measuring Alamar blue dye conversion in a fluorescence spectrophotometer. Effective concentrations at which cellular growth is inhibited by 50% (EC50) are extrapolated from the dose-response curve fit. To determine the DNA content, cell suspensions are fixed in 80% ethanol, treated for 5 minutes with 0.25% Triton X-100 in PBS, and incubated with 0.1% RNase and 10 μg/mL propidium iodide in PBS for 20 minutes at room temperature. Cell Cycle profiles are determined by flow cytometric analysis.

Animal Study: [1]

Animal Models	Female BomTac:NMRI-Foxn1nu mice grafted s.c. with HCT116, NCI-H460, or CXB1 cells
Formulation	Formulated in hydrochloric acid (0.1 N), and diluted with 0.9% NaCl, or suspended in 0.5% Natrosol 250 hydroxyethyl-cellulose
Dosages	~25 mg/kg/day
Administration	Injected i.v., or given intragastrally via gavage needle
Solubility	30% PEG400/0.5% Tween80/5% propylene glycol, 30 mg/mL
* 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.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Baboon	Dog	Monkey	Rabbit	Guinea pig	Rat	Hamster	Mouse
Weight (kg)	12	10	3	1.8	0.4	0.15	0.08	0.02
Body Surface Area (m2)	0.6	0.5	0.24	0.15	0.05	0.025	0.02	0.007
Km factor	20	20	12	12	8	6	5	3

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×	mouse Km(3)	= 11.2 mg/kg
	rat Km(6)

Chemical Information

Molecular Weight (MW)	618.81
Formula	C34H50N8O3
CAS No.	755038-65-4

Storage	3 years -20℃Powder
	6 months-80℃in solvent (DMSO, water, etc.)
Synonyms

Solubility (25°C) *	In vitro	DMSO	50 mg/mL (80.8 mM)
		Water	<1 mg/mL (
		Ethanol	124 mg/mL (200.38 mM)
	In vivo	30% PEG400/0.5% Tween80/5% propylene glycol	30 mg/mL
* <1 mg/ml means slightly soluble or insoluble. * 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.

Chemical Name	N-((1r,4r)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-4-((R)-7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-ylamino)-3-methoxybenzamide

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Product Categories : Cell Cycle > PLK Inhibitor