PHA-767491 - CAS 845714-00-3
Catalog number: 845714-00-3
Category: Inhibitor
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Molecular Formula:
C12H11N3O
Molecular Weight:
213.24
COA:
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Targets:
CDK
Description:
PHA-767491 is a potent, ATP-competitive dual cdc7/cdk9 inhibitor (IC50 values are 10 and 34 nM respectively) that prevents initiation of DNA replication.
Synonyms:
PHA-767491; PHA767491; PHA 767491.
MSDS:
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InChIKey:
DKXHSOUZPMHNIZ-UHFFFAOYSA-N
InChI:
InChI=1S/C12H11N3O/c16-12-9-7-11(8-1-4-13-5-2-8)15-10(9)3-6-14-12/h1-2,4-5,7,15H,3,6H2,(H,14,16)
Canonical SMILES:
C1CNC(=O)C2=C1NC(=C2)C3=CC=NC=C3
1.Characterization of a Dual CDC7/CDK9 Inhibitor in Multiple Myeloma Cellular Models.
Natoni A;Coyne MR;Jacobsen A;Rainey MD;O'Brien G;Healy S;Montagnoli A;Moll J;O'Dwyer M;Santocanale C Cancers (Basel). 2013 Jul 24;5(3):901-18. doi: 10.3390/cancers5030901.
Two key features of myeloma cells are the deregulation of the cell cycle and the dependency on the expression of the BCL2 family of anti-apoptotic proteins. The cell division cycle 7 (CDC7) is an essential S-phase kinase and emerging CDC7 inhibitors are effective in a variety of preclinical cancer models. These compounds also inhibit CDK9 which is relevant for MCL-1 expression. The activity and mechanism of action of the dual CDC7/CDK9 inhibitor PHA-767491 was assessed in a panel of multiple myeloma cell lines, in primary samples from patients, in the presence of stromal cells and in combination with drugs used in current chemotherapeutic regimens. We report that in all conditions myeloma cells undergo cell death upon PHA-767491 treatment and we report an overall additive effect with melphalan, bortezomib and doxorubicin, thus supporting further assessment of targeting CDC7 and CDK9 in multiple myeloma.
2.DNA Replication Dynamics and Cellular Responses to ATP Competitive CDC7 Kinase Inhibitors.
Rainey MD;Quachthithu H;Gaboriau D;Santocanale C ACS Chem Biol. 2017 Jul 21;12(7):1893-1902. doi: 10.1021/acschembio.7b00117. Epub 2017 Jun 7.
The CDC7 kinase, by phosphorylating the MCM DNA helicase, is a key switch for DNA replication initiation. ATP competitive CDC7 inhibitors are being developed as potential anticancer agents; however how human cells respond to the selective pharmacological inhibition of this kinase is controversial and not understood. Here we have characterized the mode of action of the two widely used CDC7 inhibitors, PHA-767491 and XL-413, which have become important tool compounds to explore the kinase's cellular functions. We have used a chemical genetics approach to further characterize pharmacological CDC7 inhibition and CRISPR/CAS9 technology to assess the requirement for kinase activity for cell proliferation. We show that, in human breast cells, CDC7 is essential and that CDC7 kinase activity is formally required for proliferation. However, full and sustained inhibition of the kinase, which is required to block the cell-cycle progression with ATP competitor compounds, is problematic to achieve. We establish that MCM2 phosphorylation is highly sensitive to CDC7 inhibition and, as a biomarker, it lacks in dynamic range since it is easily lost at concentrations of inhibitors that only mildly affect DNA synthesis.
3.Repurposing of the CDK inhibitor PHA-767491 as a NRF2 inhibitor drug candidate for cancer therapy via redox modulation.
Liu HY;Tuckett AZ;Fennell M;Garippa R;Zakrzewski JL Invest New Drugs. 2018 Aug;36(4):590-600. doi: 10.1007/s10637-017-0557-6. Epub 2018 Jan 3.
Oxidative stress and cellular response mechanisms such as NRF2-mediated antioxidant responses play differential roles in healthy and diseased cells. Constant generation and elimination of high levels of reactive oxygen species is a hallmark of many cancer cell types; this phenomenon is not observed during steady state of healthy cells. Manipulation of NRF2 transcriptional activity and the cellular redox homeostasis therefore has potential to be therapeutically exploitable for cancer therapy by preferentially targeting cancer cells for induction of oxidative stress. We found that the NRF2 inhibitor brusatol triggered increased oxidative stress while compromising viability and proliferation of multiple myeloma cells. Using a repurposing approach we discovered that the Cdc7/CDK9 inhibitor PHA-767491 is also a potent inhibitor of NRF2 transcriptional activity. The molecule was identified by high throughput screening of a library of about 5900 drug-like molecules. Screening assays included two cell-based assays using HepG2 hepatocellular carcinoma cells: a) A NRF2 nuclear translocation assay, and b) A NRF2 luciferase reporter assay. Validation assays were performed in multiple myeloma cells and included detection of mitochondrial superoxide levels and MTS assays.
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CAS 845714-00-3 PHA-767491

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