PF-477736

Chk1 inhibitor CAS# 952021-60-2

PF-477736

Catalog No. BCC4421----Order now to get a substantial discount!

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Chemical structure

PF-477736

3D structure

Chemical Properties of PF-477736

Cas No. 952021-60-2 SDF Download SDF
PubChem ID 16750408 Appearance Powder
Formula C22H25N7O2 M.Wt 419.48
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 125 mg/mL (297.99 mM; Need ultrasonic)
SMILES CN1C=C(C=N1)C2=NC3=C4C2=CNNC(=O)C4=CC(=C3)NC(=O)C(C5CCCCC5)N
Standard InChIKey YFNWWNRZJGMDBR-LJQANCHMSA-N
Standard InChI InChI=1S/C22H25N7O2/c1-29-11-13(9-25-29)20-16-10-24-28-21(30)15-7-14(8-17(27-20)18(15)16)26-22(31)19(23)12-5-3-2-4-6-12/h7-12,19,24H,2-6,23H2,1H3,(H,26,31)(H,28,30)/t19-/m1/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of PF-477736

DescriptionPF-477736 is a selective, potent and ATP-competitive inhibitor of Chk1 with a Ki value of 0.49 nM.
TargetsChk1VEGFR2FmsYESChk2  
IC500.49 nM(Ki)8 nM(Ki)10 nM(Ki)14 nM(Ki)47 nM(Ki)  

Protocol

Cell Assay [1]
HT29 or human umbilical vein endothelial cells are treated with gemcitabine (15 nM) or camptothecin (25 nM) for 16 h. PF 477736 (PF-00477736) is subsequently added at varying concentrations. At 4 to 48 h after the addition of PF 477736, the drug-containing medium is removed and cells are incubated in drug-free medium. When the vehicle-treated control cells are 90% confluent (8 days from plating), cells are harvested and counted by Coulter counter[1].

Animal Administration [1]
Chemotherapy agents or PF 477736 (PF-00477736) are administered by i.p. injection when tumors are 100 to 150 mm3 in volume over the designated treatment schedules. Gemcitabine is administered over a range of doses including the maximum tolerated dose (MTD) in mice according to a once every 3 days for four treatments (q3d × 4) schedule. PF 477736 is administered over a range of doses (4-60 mg/kg) according to the q3d × 4 schedule beginning 24 h after gemcitabine. MTD of PF 477736 is determined to be 40 mg/kg considering the severity of the behavioral response on i.p. administration and body weight loss of 5% to 10%. For cytotoxic agents, MTD is the occurrence of mean body weight loss of 5% to 10%[1].

References:
[1]. Blasina A, et al. Breaching the DNA damage checkpoint via PF-00477736, a novel small-molecule inhibitor of checkpoint kinase 1. Mol Cancer Ther. 2008 Aug;7(8):2394-404 [2]. Ashwell S, et al. Keeping checkpoint kinases in line: new selective inhibitors in clinical trials. Expert Opin Investig Drugs. 2008 Sep;17(9):1331-40.

PF-477736 Dilution Calculator

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PF-477736 Molarity Calculator

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Preparing Stock Solutions of PF-477736

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.3839 mL 11.9195 mL 23.839 mL 47.6781 mL 59.5976 mL
5 mM 0.4768 mL 2.3839 mL 4.7678 mL 9.5356 mL 11.9195 mL
10 mM 0.2384 mL 1.192 mL 2.3839 mL 4.7678 mL 5.9598 mL
50 mM 0.0477 mL 0.2384 mL 0.4768 mL 0.9536 mL 1.192 mL
100 mM 0.0238 mL 0.1192 mL 0.2384 mL 0.4768 mL 0.596 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on PF-477736

PF-477736 is a potent, selective ATP-competitive and small-molecule inhibitor of Chk1 with a Ki of 0.49±0.29nM for the in vitro kinase activity of Chk1 [1].

PF-477736 has shown a selective inhibition of Chk1 with the IC50 values of 0.49nM, 9.9μM and 47nM for Chk1, CDK1 and Chk2, respectively. In a dot-blot assay, PF-477736 has been reported to inhibit camptothecin-induced G2 arrest with the EC50 values of 45nM, 38nM and 42nM in P53-mutated human lymphoma CA46 cells, HeLa cells and HT29 cells. Apart from these, PF-477736 has been found to selectively target p53-defective cancer cells while having minimal cytotoxic effects on normal (p53-competent) cells. In addition, PF-00477736 has been revealed to dose-dependently enhance the antitumor activity of a MTD of gemcitabine with no apparent exacerbation of systemic toxicity as assessed by monitoring body weight in the Colo205 xenograft [1].

References:
[1] Blasina A1, Hallin J, Chen E, Arango ME, Kraynov E, Register J, Grant S, Ninkovic S, Chen P, Nichols T, O'Connor P, Anderes K. Breaching the DNA damage checkpoint via PF-00477736, a novel small-molecule inhibitor of checkpoint kinase 1. Mol Cancer Ther. 2008 Aug;7(8):2394-404.

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References on PF-477736

Thymineless Death by the Fluoropyrimidine Polymer F10 Involves Replication Fork Collapse and Is Enhanced by Chk1 Inhibition.[Pubmed:30439567]

Neoplasia. 2018 Dec;20(12):1236-1245.

We are developing the fluoropyrimidine polymer F10 to overcome limitations of 5-fluorouracil (5-FU) that result from inefficient metabolism to 5-fluoro-2'-deoxyuridine-5'-mono- and tri-phosphate, the deoxyribonucleotide metabolites that are responsible for 5-FU's anticancer activity. F10 is much more cytotoxic than 5-FU to colorectal cancer (CRC) cells; however, the mechanism of enhanced F10 cytotoxicity remains incompletely characterized. Using DNA fiber analysis, we establish that F10 decreases replication fork velocity and causes replication fork collapse, while 1000-fold excess of 5-FU is required to achieve similar endpoints. Treatment of HCT-116 cells with F10 results in Chk1 phosphorylation and activation of intra-S-phase checkpoint. Combining F10 with pharmacological inhibition of Chk1 with either PF-477736 or prexasertib in CRC cells enhanced DNA damage relative to single-agent treatment as assessed by gammaH2AX intensity and COMET assay. PF-477736 or prexasertib co-treatment also inhibited upregulation of Rad51 levels in response to F10, resulting in reduced homologous repair. siRNA knockdown of Chk1 also increased F10-induced DNA damage assessed and sensitized CRC cells to F10. However, Chk1 knockdown did not inhibit Rad51 upregulation by F10, indicating that the scaffolding activity of Chk1 imparts activity in DNA repair distinct from Chk1 enzymatic activity. Our results indicate that F10 is cytotoxic to CRC cells in part through DNA damage subsequent to replication fork collapse. F10 is ~1000-fold more potent than 5-FU at inducing replication-mediated DNA damage which correlates with the increased overall potency of F10 relative to 5-FU. F10 efficacy can be enhanced by pharmacological inhibition of Chk1.

DUOXA1-mediated ROS production promotes cisplatin resistance by activating ATR-Chk1 pathway in ovarian cancer.[Pubmed:29704517]

Cancer Lett. 2018 Aug 1;428:104-116.

The acquisition of resistance is a major obstacle to the clinical use of platinum drugs for ovarian cancer treatment. Increase of DNA damage response is one of major mechanisms contributing to platinum-resistance. However, how DNA damage response is regulated in platinum-resistant ovarian cancer cells remains unclear. Using quantitative high throughput combinational screen (qHTCS) and RNA-sequencing (RNA-seq), we show that dual oxidase maturation factor 1 (DUOXA1) is overexpressed in platinum-resistant ovarian cancer cells, resulting in over production of reactive oxygen species (ROS). Elevated ROS level sustains the activation of ATR-Chk1 pathway, leading to resistance to cisplatin in ovarian cancer cells. Moreover, using qHTCS we identified two Chk1 inhibitors (PF-477736 and AZD7762) that re-sensitize resistant cells to cisplatin. Blocking this novel pathway by inhibiting ROS, DUOXA1, ATR or Chk1 effectively overcomes cisplatin resistance in vitro and in vivo. Significantly, the clinical studies also confirm the activation of ATR and DOUXA1 in ovarian cancer patients, and elevated DOUXA1 or ATR-Chk1 pathway correlates with poor prognosis. Taken together, our findings not only reveal a novel mechanism regulating cisplatin resistance, but also provide multiple combinational strategies to overcome platinum-resistance in ovarian cancer.

Chk1 inhibition as a novel therapeutic strategy for treating triple-negative breast and ovarian cancers.[Pubmed:25104095]

BMC Cancer. 2014 Aug 7;14:570.

BACKGROUND: Chk1 inhibitors are currently in clinical trials as putative potentiators of cytotoxic chemotherapy drugs. Chk1 inhibitors may exhibit single agent anti-tumor activity in cancers with underlying DNA repair, DNA damage response or DNA replication defects. METHODS: Here we describe the cellular effects of the pharmacological inhibition of the checkpoint kinase Chk1 by the novel inhibitor V158411 in triple-negative breast cancer and ovarian cancer. Cytotoxicity, the effect on DNA damage response and cell cycle along with the ability to potentiate gemcitabine and cisplatin cytotoxicity in cultured cells was investigated. Western blotting of proteins involved in DNA repair, checkpoint activation, cell cycle and apoptosis was used to identify potential predictive biomarkers of Chk1 inhibitor sensitivity. RESULTS: The Chk1 inhibitors V158411, PF-477736 and AZD7762 potently inhibited the proliferation of triple-negative breast cancer cells as well as ovarian cancer cells, and these cell lines were sensitive compared to ER positive breast and other solid cancer cells lines. Inhibition of Chk1 in these sensitive cell lines induced DNA damage and caspase-3/7 dependent apoptosis. Western blot profiling identified pChk1 (S296) as a predictive biomarker of Chk1 inhibitor sensitivity in ovarian and triple-negative breast cancer and pH2AX (S139) in luminal breast cancer. CONCLUSIONS: This finding suggests that Chk1 inhibitors either as single agents or in combination chemotherapy represents a viable therapeutic option for the treatment of triple-negative breast cancer. pChk1 (S296) tumor expression levels could serve as a useful biomarker to stratify patients who might benefit from Chk1 inhibitor therapy.

Gemcitabine and CHK1 inhibition potentiate EGFR-directed radioimmunotherapy against pancreatic ductal adenocarcinoma.[Pubmed:24838526]

Clin Cancer Res. 2014 Jun 15;20(12):3187-97.

PURPOSE: To develop effective combination therapy against pancreatic ductal adenocarcinoma (PDAC) with a combination of chemotherapy, CHK1 inhibition, and EGFR-targeted radioimmunotherapy. EXPERIMENTAL DESIGN: Maximum tolerated doses were determined for the combination of gemcitabine, the CHK1 inhibitor PF-477736, and Lutetium-177 ((177)Lu)-labeled anti-EGFR antibody. This triple combination therapy was investigated using PDAC models from well-established cell lines, recently established patient-derived cell lines, and fresh patient-derived xenografts. Tumors were investigated for the accumulation of (177)Lu-anti-EGFR antibody, survival of tumor-initiating cells, induction of DNA damage, cell death, and tumor tissue degeneration. RESULTS: The combination of gemcitabine and CHK1 inhibitor PF-477736 with (177)Lu-anti-EGFR antibody was tolerated in mice. This triplet was effective in established tumors and prevented the recurrence of PDAC in four cell line-derived and one patient-derived xenograft model. This exquisite response was associated with the loss of tumor-initiating cells as measured by flow cytometric analysis and secondary implantation of tumors from treated mice into treatment-naive mice. Extensive DNA damage, apoptosis, and tumor degeneration were detected in the patient-derived xenograft. Mechanistically, we observed CDC25A stabilization as a result of CHK1 inhibition with consequent inhibition of gemcitabine-induced S-phase arrest as well as a decrease in canonical (ERK1/2 phosphorylation) and noncanonical EGFR signaling (RAD51 degradation) as a result of EGFR inhibition. CONCLUSIONS: Our study developed an effective combination therapy against PDAC that has potential in the treatment of PDAC.

Description

PF 477736 is a potent, selective ATP-competitive inhibitor of Chk1, with a Ki of 0.49 nM, 100-fold selectivity versus Chk2 (Ki, 47 nM).

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