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755038-65-4 molecular structure
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4-{[(7R)-7-ethyl-5-methyl-6-oxo-8-(propan-2-yl)-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxy-N-[(1r,4r)-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl]benzamide

ChemBase ID: 73084
Molecular Formular: C34H50N8O3
Molecular Mass: 618.8126
Monoisotopic Mass: 618.4005875
SMILES and InChIs

SMILES:
[C@H]1(C(=O)N(c2c(N1C(C)C)nc(nc2)Nc1ccc(cc1OC)C(=O)N[C@@H]1CC[C@H](CC1)N1CCN(CC1)CC1CC1)C)CC
Canonical SMILES:
CC[C@H]1N(C(C)C)c2nc(ncc2N(C1=O)C)Nc1ccc(cc1OC)C(=O)N[C@@H]1CC[C@H](CC1)N1CCN(CC1)CC1CC1
InChI:
InChI=1S/C34H50N8O3/c1-6-28-33(44)39(4)29-20-35-34(38-31(29)42(28)22(2)3)37-27-14-9-24(19-30(27)45-5)32(43)36-25-10-12-26(13-11-25)41-17-15-40(16-18-41)21-23-7-8-23/h9,14,19-20,22-23,25-26,28H,6-8,10-13,15-18,21H2,1-5H3,(H,36,43)(H,35,37,38)/t25-,26-,28-/m1/s1
InChIKey:
SXNJFOWDRLKDSF-STROYTFGSA-N

Cite this record

CBID:73084 http://www.chembase.cn/molecule-73084.html

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NAMES AND DATABASE IDS

NAMES AND DATABASE IDS

Names Database IDs
IUPAC name
4-{[(7R)-7-ethyl-5-methyl-6-oxo-8-(propan-2-yl)-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxy-N-[(1r,4r)-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl]benzamide
IUPAC Traditional name
4-{[(7R)-7-ethyl-8-isopropyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino}-3-methoxy-N-[(1r,4r)-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl]benzamide
Synonyms
Volasertib
BI6727
CAS Number
755038-65-4
PubChem SID
162038004
PubChem CID
10461508

DATA SOURCES

DATA SOURCES

All Sources Commercial Sources Non-commercial Sources
Data Source Data ID Price
Selleck Chemicals
S2235 external link Add to cart Please log in.
Data Source Data ID
PubChem 10461508 external link

CALCULATED PROPERTIES

CALCULATED PROPERTIES

JChem
Acid pKa 11.448011  H Acceptors
H Donor LogD (pH = 5.5) 0.8745856 
LogD (pH = 7.4) 2.5038016  Log P 4.2043643 
Molar Refractivity 178.3426 cm3 Polarizability 67.61261 Å3
Polar Surface Area 106.17 Å2 Rotatable Bonds 10 
Lipinski's Rule of Five false 

PROPERTIES

PROPERTIES

Safety Information Pharmacology Properties Product Information Bioassay(PubChem)
Storage Condition
-20°C expand Show data source
Target
PLK expand Show data source
Salt Data
Free Base expand Show data source

DETAILS

DETAILS

Selleck Chemicals Selleck Chemicals
Selleck Chemicals - S2235 external link
Research Area
Description Caner
Biological Activity
Description BI6727 (Volasertib) is a highly potent Plk1 inhibitor with IC50 of 0.87 nM.
Targets Plk1
IC50 0.87 nM [1]
In Vitro 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. [1] 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. [2] BI6727 induces growth arrest of Daoy and ONS-76 medulloblastoma cells similar to BI 2536. [3]
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. [1] In in vivo studies, BI6727 shows better toxicity and pharmacokinetic profile compared to BI2536. [3]
Clinical Trials A Phase I study of BI6727 in Japanese patients with advanced solid tumors is currently ongoing.
Features BI6727 has a high volume of distribution, indicating good tissue penetration, and a long terminal half-life.
Combination Therapy
Description A Phase I study of BI6727 in combination with oral BIBW 2992 (Afatinib) in patients with advanced solid tumors is currently ongoing.
Protocol
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
Methods 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
Doses ~25 mg/kg/day
Administration Injected i.v., or given intragastrally via gavage needle
References
[1] Rudolph D, et al. Clin Cancer Res, 2009, 15(9), 3094-3102.
[2] Grinshtein N, et al. Cancer Res, 2011, 71(4), 1385-1395.
[3] Harris PS, et al. BMC Cancer, 2012, 12, 80.

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