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827022-32-2 molecular structure
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6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H,8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride

ChemBase ID: 72521
Molecular Formular: C24H30ClN7O2
Molecular Mass: 483.9937
Monoisotopic Mass: 483.21495092
SMILES and InChIs

SMILES:
n1c(nc2c(c1)c(c(c(=O)n2C1CCCC1)C(=O)C)C)Nc1ncc(cc1)N1CCNCC1.Cl
Canonical SMILES:
CC(=O)c1c(C)c2cnc(nc2n(c1=O)C1CCCC1)Nc1ccc(cn1)N1CCNCC1.Cl
InChI:
InChI=1S/C24H29N7O2.ClH/c1-15-19-14-27-24(28-20-8-7-18(13-26-20)30-11-9-25-10-12-30)29-22(19)31(17-5-3-4-6-17)23(33)21(15)16(2)32;/h7-8,13-14,17,25H,3-6,9-12H2,1-2H3,(H,26,27,28,29);1H
InChIKey:
STEQOHNDWONVIF-UHFFFAOYSA-N

Cite this record

CBID:72521 http://www.chembase.cn/molecule-72521.html

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NAMES AND DATABASE IDS

NAMES AND DATABASE IDS

Names Database IDs
IUPAC name
6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H,8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride
IUPAC Traditional name
6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}pyrido[2,3-d]pyrimidin-7-one hydrochloride
Synonyms
PD 0332991
CAS Number
827022-32-2
PubChem SID
162037446
PubChem CID
11431660

DATA SOURCES

DATA SOURCES

All Sources Commercial Sources Non-commercial Sources
Data Source Data ID Price
Selleck Chemicals
S1116 external link Add to cart Please log in.
Data Source Data ID
PubChem 11431660 external link

CALCULATED PROPERTIES

CALCULATED PROPERTIES

JChem
Acid pKa 11.338534  H Acceptors
H Donor LogD (pH = 5.5) -0.2954974 
LogD (pH = 7.4) 1.2965542  Log P 2.770733 
Molar Refractivity 127.4663 cm3 Polarizability 47.58873 Å3
Polar Surface Area 103.35 Å2 Rotatable Bonds
Lipinski's Rule of Five true 

PROPERTIES

PROPERTIES

Physical Property Safety Information Pharmacology Properties Product Information Bioassay(PubChem)
Solubility
DMSO expand Show data source
Storage Condition
-20°C expand Show data source
Target
CDK expand Show data source
Salt Data
hydrochloride expand Show data source

DETAILS

DETAILS

Selleck Chemicals Selleck Chemicals
Selleck Chemicals - S1116 external link
Biological Activity
Description PD 0332991 is a highly selective inhibitor of CDK4/cyclin D1 and CDK6/cyclin D2 with IC50 of 11 nM and 16 nM, respectively.
Targets CDK4/cyclin D1 CDK4/cyclin D2
IC50 11 nM 16 nM [1]
In Vitro PD 0332991 has little effect on other protein kinases including EGFR, FGFR, PGFR, IR. PD 0332991 is a non-ATP competitive inhibitor of Cdk4. PD 0332991 inhibits MDA-MB-435 breast carcinoma cells with IC50 of 66 nM, which is due to reduced Rb phosphorylation at Ser780. PD 0332991 inhibits thymidine incorporation into the DNA of Rb-positive human breast, colon, and lung carcinomas as well as human leukemias, with IC50 values ranging from 0.04 to 0.17 μM. PD 0332991 shows no activity in Rb-negative cells. PD 0332991 causes an accumulation of cells in G1 in MDA-MB-453 breast and Colo-205 carcinoma cells. [1] PD 0332991 also shows activity in 5T33MM myeloma cells (immunocompetent model) and sensitizes the cells to killing by bortezomib. [2] PD 0332991 inhibits luminal ER-positive as well as HER2-amplified breast cancer cell lines including MDA-MB-175, ZR-75-30, CAMA-1, MDA-MB-134, HCC-202 and UACC-893. PD 0332991 enhances the activity of tamoxifen and trastuzumab in these cell lines. PD 0332991 enhances the sensitivity of tamoxifen in the MCF7 tamoxifen-resistant cells. [3] A recent study shows that PD 0332991 could suppress malignant rhabdoid tumor (MRT) cell lines including MP-MRT-AN, KP-MRT-RY, G401, KP-MRT-NS and the sensitivity of the MRT cell lines to PD 0332991 is inversely correlated with expression of p16. [4]
In Vivo PD 0332991 indicates complete tumor stasis in a MDA-MB-435 xenograft at 150 mg/kg. PD 0332991 also shows broad-spectrum antitumor activity in multiple human tumor xenografts by eliminating phospho-Rb and the proliferative marker Ki-67 from tumor tissue and down-regulation of genes under the transcriptional control of E2F. [1]
Clinical Trials PD 0332991 is currently under Phase II clinical trial for advanced or metastatic liposarcoma.
Features PD 0332991 itself does not kill cancer cells - just halts their growth and could be used in which glioblastoma has come back after treatment with temozolomide, a chemotherapy used in many cancer patients.
Protocol
Kinase Assay [1]
Cdk Assays A stock solution of PD0332991 is prepared in DMSO. CDK assays are performed in 96-well filter plates. All CDK-cyclin kinase complexes are expressed in insect cells through baculovirus infection and purified. The substrate for the assays is a fragment (amino acids 792–928) of pRb fused to GST (GST·RB-Cterm). The total volume in each well is 0.1 mL containing a final concentration of 20 mM Tris-HCl, pH 7.4, 50 mM NaCl, 1 mM dithiothreitol, 10 mM MgCl2, 25 μM ATP (for CDK4-cyclin D1, CDK6-cyclin D2, and CDK6-cyclin D3) or 12 μM ATP (for CDK2-cyclin E, CDK2-cyclin A, and CDC2-cyclin B) containing 0.25 μCi of [γ-32P]ATP, 20 ng of enzyme, 1 μg of GST·RB-Cterm, and PD 0332991 (0.001-0.1μM). All components except the [γ-32P]ATP are added to the wells, and the plate is placed on a plate mixer for 2 min. The reaction is started by adding the [γ-32P]ATP and the plate is incubated at 25 °C for 15 min. The reaction is terminated by addition of 0.1 mL of 20% trichloroacetic acid and the plate is kept at 4 ?°C for at least 1 hour to allow the substrate to precipitate. The wells are then washed 5 times with 0.2 mL of 10% trichloroacetic acid and radioactive incorporation is determined with a β plate counter.
Cell Assay [1]
Cell Lines Tumor cell lines including MDA-MB-435, ZR-75-1, T-47D, MCF-7, H1299, Colo-205, MDA-MB-468, H2009, CRRF-CEM and K562
Concentrations 0.01-1 μM
Incubation Time 24 hours
Methods Cells are seeded at 2 × 104 per well in a 96-well plate and incubated overnight. PD 0332991 (0.01-1 μM) is added to the wells and incubated at 37 °C for another 24 hours. [14C]Thymidine (0.1 μCi) is added to each well and incorporation of the radiolabel is allowed to proceed for 72 hours. Incorporated radioactivity is determined with a β plate counter.
Animal Study [1]
Animal Models Advanced stage human tumor xenografts including Colo-205, MDA-MB-435 breast, SF-295 glioblastoma, ZR-75-1 breast, PC-3 prostate, H125 lung, SW-620 colon, H23 lung and MDA-MB-468 breast (Rb negative) are established in severe combined immunodeficient mice.
Formulation Dissolved in sodium lactate buffer (50 mM, pH 4.0)
Doses 0-150 mg/kg
Administration Given by gavage
References
[1] Fry DW, et al. Mol Cancer Ther, 2004, 3(11), 1427-1438.
[2] Menu E, et al. Cancer Res, 2008, 68(14), 5519-5523.
[3] Finn RS, et al. Breast Cancer Res, 2009, 11(5), R77.
[4] Katsumi Y, et al. Biochem Biophys Res Commun, 2011, 413(1), 62-68.

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