PHA-767491 - CAS 845714-00-3
Catalog number: 845714-00-3
Category: Inhibitor
Please be kindly noted products are not for therapeutic use. We do not sell to patients.
Molecular Formula:
Molecular Weight:
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.
PHA-767491; PHA767491; PHA 767491.
Canonical SMILES:
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.
Molecular Weight Calculator Molarity Calculator Solution Dilution Calculator

Related CDK Products

CAS 719277-26-6 TG003

(CAS: 719277-26-6)

TG003 is a potent, ATP-competitive inhibitor of Clk-family kinases. TG003 inhibited SF2/ASF-dependent splicing of beta-globin pre-mRNA in vitro by suppression o...

CAS 212779-48-1 NG 52

NG 52
(CAS: 212779-48-1)

NG 52 is a tri-substituted purine that binds to the ATP-binding site of yeast cyclin-dependent kinases, inhibiting Cdc28p and Pho85p (IC50s = 7 and 2 µM, respec...

CAS 1374639-79-8 LEE011 succinate hydrate

LEE011 succinate hydrate
(CAS: 1374639-79-8)

LEE011 succinate hydrate is an orally available cyclin-dependent kinase (CDK) inhibitor targeting cyclin D1/CDK4 and cyclin D3/CDK6 cell cycle pathway, with pot...

Ca2+ Channel Agonist 1
(CAS: 1402821-24-2)

A Ca2+ Channel Agonist that selectively acting on N-type Ca2+ channel and also be found to restrain the cdk activity at some extent. IC50: 14.23 uM (EC50, Ca2+ ...

(CAS: 1604810-84-5)

THZ2, an analog of THZ1, with the potential to treat Triple-negative breast cancer (TNBC), it is a potent and selective CDK7 inhibitor which overcomes the insta...

CAS 1397219-81-6 BS-181 HCl

BS-181 HCl
(CAS: 1397219-81-6)

BS-181 HCl is a highly selective CDK7 inhibitor with IC50 of 21 nM. It is more than 40-fold selective for CDK7 than CDK1, 2, 4, 5, 6, or 9.

CAS 1092443-52-1 BS181

(CAS: 1092443-52-1)

BS-181 is a highly selective CDK inhibitor for CDK7 with an IC(50) of 21 nmol/L. Testing of other CDKs as well as another 69 kinases showed that BS-181 only inh...

(CAS: 1391855-95-0)

CDK9-IN-6, one of the CDK9 inhibitors, probably have potential activity in influencing cell cycle of T-type cells.

CAS 844442-38-2 AT-7519

(CAS: 844442-38-2)

AT-7519 is an orally bioavailable small molecule CDK inhibitor with potential antineoplastic activity. AT7519M selectively binds to and inhibits cyclin dependen...

CAS 142273-20-9 Kenpaullone

(CAS: 142273-20-9)

Kenpaullone is a potent inhibitor of CDK1/cyclin B (IC50 = 400 nM), CDK2/cyclin A (IC50 = 680 nM), CDK2/cyclin E (IC50 = 7.5 uM) and CDK5/p25 (IC50 = 850 nM). K...

CAS 1269815-17-9 CDK-IN-2

(CAS: 1269815-17-9)

CDK-IN-2 is a potent and sepecific CDK inhibitor.

CAS 845714-00-3 PHA-767491

(CAS: 845714-00-3)

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.

CAS 827022-32-2 Palbociclib HCl

Palbociclib HCl
(CAS: 827022-32-2)

Palbociclib, also known as PD0332991, is an orally available pyridopyrimidine-derived cyclin-dependent kinase (CDK) inhibitor with potential antineoplastic acti...

CAS 718630-59-2 PHA-793887

(CAS: 718630-59-2)

PHA-793887 is an inhibitor of multiple cyclin dependent kinases (CDK) with activity against CDK2, CDK1 and CDK4. Although toxicity was acceptable at initial dos...

(CAS: 1354037-26-5)

KH-CB19, a CLK1/CLK4 inhibitor, has been found to probably restrain the phosphorylation of serine- and arginine-rich (SR) proteins. IC50: 20 nM for CLK1.

CAS 161058-83-9 NU2058

(CAS: 161058-83-9)

NU2058 is a potent CDK inhibitor. which has CDK2 IC(50)=17 microM and CDK1 IC(50)=26 microM.

CAS 872573-93-8 RO-3306

(CAS: 872573-93-8)

RO-3306 is a CDK1 inhibitor with potential anticancer activity. Treatment of growing AML cells with RO-3306 induced G2/M-phase cell cycle arrest and apoptosis ...

CAS 1263369-28-3 CDK9-IN-2

(CAS: 1263369-28-3)

CDK9-IN-2 is a novel cyclin-dependent kinase 9(CDK9) inhibitor.

CAS 377090-84-1 SU9516

(CAS: 377090-84-1)

SU 9516 is a potent, selective cdk2 inhibitor (IC50 values are 0.022, 0.04, >10, >10, 18 and >100 μM for cdk2, cdk1, cdk4, PKC, p38, PDGFR and EGFR respectively...

CAS 902156-99-4 NVP-LCQ195

(CAS: 902156-99-4)

NVP-LCQ195 is a small molecule heterocyclic inhibitor of CDK1, CDK2, CDK3 and CDK5. It induced cell cycle arrest and eventual apoptotic cell death of MM cells, ...

Chemical Structure

CAS 845714-00-3 PHA-767491

Quick Inquiry

Verification code

Featured Items