PD 0332991 HCl

Information	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 an 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.

Information

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 an 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.

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 ℃ for 15 min. The reaction is terminated by addition of 0.1 mL of 20% trichloroacetic acid and the plate is kept at 4 ℃ 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 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
Method:	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 ℃ 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.

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

Method:

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 ℃ 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 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)
Dosages:	0-150 mg/kg
Administration:	Given by gavage

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)

Dosages:

0-150 mg/kg

Administration:

Given by gavage

Molecular Weight (WM):	483.99
Formula:	C₂₄H₂₉N₇O₂.HCl
CAS No.:	827022-32-2
Synonyms:	N/A

Molecular Weight (WM):

483.99

Formula:

C₂₄H₂₉N₇O₂.HCl

CAS No.:

827022-32-2

Synonyms:

N/A

Dissolve in (25°C):	DMSO ≥25mg/mL
	Water ≥90mg/mL
	Ethanol ≥4mg/mL
Storage:	2 years-20°CPowder
	1 week-4°Cin DMSO
	1 month-80°in DMSO

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Biological Activity

Protocol (Only for Reference)

Kinase Assay: [1]

Cell Assay: [1]

Animal Study:[1]

References

Chemical Information

Quality Control & MSDS

Research Area

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Secondary Antibodies

Loading Control Antibodies

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Kinase Assay: ^[1]

Cell Assay: ^[1]

Animal Study:^[1]

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