PHA-767491

For research use only.

Catalog No.S2742 Synonyms: CAY10572, NMS 1116354

26 publications

PHA-767491 Chemical Structure

CAS No. 942425-68-5

PHA-767491 (CAY10572, NMS 1116354) is a potent ATP-competitive dual Cdc7/CDK9 inhibitor with IC50 of 10 nM and 34 nM in cell-free assays, respectively.It displays ~20-fold selectivity against CDK1/2 and GSK3-β, 50-fold selectivity against MK2 and CDK5, 100-fold selectivity against PLK1 and CHK2.

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Selleck's PHA-767491 has been cited by 26 publications

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Biological Activity

Description PHA-767491 (CAY10572, NMS 1116354) is a potent ATP-competitive dual Cdc7/CDK9 inhibitor with IC50 of 10 nM and 34 nM in cell-free assays, respectively.It displays ~20-fold selectivity against CDK1/2 and GSK3-β, 50-fold selectivity against MK2 and CDK5, 100-fold selectivity against PLK1 and CHK2.
Features The first inhibitor that directly affects the mechanisms controlling initiation as opposed to elongation in DNA replication.
Targets
Cdc7 [1]
(Cell-free assay)
CDK9 [1]
(Cell-free assay)
GSK-3β [1]
(Cell-free assay)
CDK2 [1]
(Cell-free assay)
CDK1 [1]
(Cell-free assay)
10 nM 34 nM 220 nM 240 nM 250 nM
In vitro

PHA-767491 displays approximately 20-fold selectivity for Cdk1, Cdk2 and GSK3-β, 50-fold selectivity for MK2 and Cdk5 and 100-fold selectivity for PLK1 and CHK2. PHA-767491 inhibits cell proliferation in a variety of human cell lines with IC50 of 0.86 μM for SF-268 to 5.87 μM for K562, and significantly induces apoptosis in a p53-independent manner in almost all cell lines in contrast with 5-FU or gemcitabine which only works in a few of cell lines. Unlike current DNA synthesis inhibitors, PHA-767491 treatment at 5 μM blocks the initiation of DNA replication but not replication fork progression, due to specific inhibition of Cdc7 kinase and Mcm2 phosphorylation at the Cdc7-dependent Ser40 site. [1] The up-regulated Mcl-1 levels in ABT-737-resistant OCI-LY1 and SU-DHL-4 cells can be significantly decreased by PHA-767491 treatment at 3 μM possibly due to the inhibition of Cdk9, leading to the restoration of the sensitivity to ABT-737. [2] The direct mitochondrial dependent pro-apoptosis effect of PHA-767491 is also observed when applied at 1 μM in quiescent chronic lymphocytic leukemia (CLL) cells through the similar mechanism with EC50 of 0.34-0.97 μM. While in proliferating CLL cells stimulated by CD154 and interleukin-4, PHA-767491 treatment at 5 μM abolishes DNA synthesis by inhibiting Cdc7 rather than triggering cell death. [3]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
human SF268 cells NH7JNXpRem:uaX\ldoF1cW:wIHHzd4F6 M1XxUFczKGh? Ml;uRY51cXC{b3zp[oVz[XSrdnWgZYN1cX[rdImgZYdicW6|dDDwOVMh\GWoaXPp[Y51KGi3bXHuJHNHOjZ6IHPlcIx{KGGodHXyJFczKGi{czygTWM2OD1yLki2JO69VQ>? NUjtWmV4OTh2Nkm4NFk>
human HCT116 cells MWTQdo9tcW[ncnH0bY9vKGG|c3H5 MmPEO|IhcA>? MX;BcpRqeHKxbHnm[ZJifGm4ZTDhZ5Rqfmm2eTDh[4FqdnO2IHj1cYFvKEiFVEGxOkBk\WyuczDlfJBz\XO|aX7nJJA2OyCpZX7lJIFnfGW{IEeyJIhzeyCkeTDwdo9tcW[ncnH0bZZmKGG|c3H5MEBKSzVyPUCuPVch|ryP MYGxPFQ3QThyOR?=
human HCT16 cells NYfURYJEWHKxbHnm[ZJifGmxbjDhd5NigQ>? MW[3NkBp MnLMRY51cXC{b3zp[oVz[XSrdnWgZYN1cX[rdImgZYdicW6|dDDoeY1idiCKQ2SxOkBk\WyuczDh[pRmeiB5MjDodpMh[nlibIXjbYZmemG|ZTDiZZNm\CCjc4PhfUwhUUN3ME2xJO69VQ>? NHv0OHQyQTFzNUi0OS=>
human SW403 cells NUiwUopnWHKxbHnm[ZJifGmxbjDhd5NigQ>? M2fsdVczKGh? NWTWRZU4SW62aYDyc4xq\mW{YYTpeoUh[WO2aY\peJkh[WejaX7zeEBpfW2jbjDTW|QxOyClZXzsd{Bi\nSncjC3NkBpenNiYomgcJVkcW[ncnHz[UBj[XOnZDDhd5NigSxiSVO1NF0yKM7:TR?= NYTCZmxVOTlzMUW4OFU>
human A2780 cells NVrjfYREWHKxbHnm[ZJifGmxbjDhd5NigQ>? MljNO|IhcA>? MkTxRY51cXC{b3zp[oVz[XSrdnWgZYN1cX[rdImgZYdicW6|dDDoeY1idiCDMke4NEBk\WyuczDlfJBz\XO|aX7nJJA2OyCpZX7lJIFnfGW{IEeyJIhzeyCkeTDwdo9tcW[ncnH0bZZmKGG|c3H5MEBKSzVyPUGuNFch|ryP M3TxWlE5PDZ7OEC5
human SW48 cells MknYVJJwdGmoZYLheIlwdiCjc4PhfS=> M1;nW|czKGh? NYfUXGF3SW62aYDyc4xq\mW{YYTpeoUh[WO2aY\peJkh[WejaX7zeEBpfW2jbjDTW|Q5KGOnbHzzJIFnfGW{IEeyJIhzeyCkeTDseYNq\mW{YYPlJIJie2WmIHHzd4F6NCCLQ{WwQVEvOiEQvF2= Mk[wNVkyOTV6NEW=
human MCF7 cells MVvQdo9tcW[ncnH0bY9vKGG|c3H5 NUfKW|I6PzJiaB?= M3r2PGFvfGmycn;sbYZmemG2aY\lJIFkfGm4aYT5JIFo[Wmwc4SgbJVu[W5iTVPGO{Bk\WyuczDh[pRmeiB5MjDodpMh[nlibIXjbYZmemG|ZTDiZZNm\CCjc4PhfUwhUUN3ME2xMlMh|ryP Mnj6NVkyOTV6NEW=
human U2OS cells MUfQdo9tcW[ncnH0bY9vKGG|c3H5 NEHtSGs4OiCq M3nuN2FvfGmycn;sbYZmemG2aY\lJIFkfGm4aYT5JIFo[Wmwc4SgbJVu[W5iVULPV{Bk\WyuczDlfJBz\XO|aX7nJJA2OyCpZX7lJIFnfGW{IEeyJIhzeyCkeTDwdo9tcW[ncnH0bZZmKGG|c3H5MEBKSzVyPUGuOFkh|ryP MUGxPFQ3QThyOR?=
human COLO205 cells NWfWcHBMWHKxbHnm[ZJifGmxbjDhd5NigQ>? MmXiO|IhcA>? MkfHRY51cXC{b3zp[oVz[XSrdnWgZYN1cX[rdImgZYdicW6|dDDoeY1idiCFT1zPNlA2KGOnbHzzJIFnfGW{IEeyJIhzeyCkeTDseYNq\mW{YYPlJIJie2WmIHHzd4F6NCCLQ{WwQVEvPSEQvF2= NInQPGcyQTFzNUi0OS=>
human OVCAR8 cells MnHxVJJwdGmoZYLheIlwdiCjc4PhfS=> MkfNO|IhcA>? NFzsc|RCdnSrcILvcIln\XKjdHn2[UBi[3Srdnn0fUBi\2GrboP0JJA2OyCmZX\pZ4lmdnRiaIXtZY4hV1[FQWK4JINmdGy|IHHmeIVzKDd{IHjyd{BjgSCycn;sbYZmemG2aY\lJIF{e2G7LDDJR|UxRTFwNU[g{txO MkmwNVg1Pjl6MEm=
human L363 cells NYrEXpl1WHKxbHnm[ZJifGmxbjDhd5NigQ>? NXvDcnBbPzJiaB?= MlrKRY51cXC{b3zp[oVz[XSrdnWgZYN1cX[rdImgZYdicW6|dDDoeY1idiCOM{[zJINmdGy|IHHmeIVzKDd{IHjyd{BjgSCudXPp[oVz[XOnIHLhd4VlKGG|c3H5MEBKSzVyPUGuOkDPxE1? MX[xPVEyPTh2NR?=
human NHDF cells M4\rPHBzd2yrZnXyZZRqd25iYYPzZZk> MoT6O|IhcA>? MWLBcpRqeHKxbHnm[ZJifGm4ZTDhZ5Rqfmm2eTDh[4FqdnO2IHj1cYFvKE6KRF[gZ4VtdHNiYX\0[ZIhPzJiaILzJIJ6KGy3Y3nm[ZJie2ViYnHz[YQh[XO|YYmsJGlEPTB;MT62JO69VQ>? NFjTemIyQTFzNUi0OS=>
human NCI-H929 cells NX;ZO3V3WHKxbHnm[ZJifGmxbjDhd5NigQ>? NYTEeHNnPzJiaB?= M4L4XGFvfGmycn;sbYZmemG2aY\lJIFkfGm4aYT5JIFo[Wmwc4SgbJVu[W5iTlPJMWg6OjliY3XscJMh[W[2ZYKgO|IhcHK|IHL5JIx2[2moZYLhd4Uh[mG|ZXSgZZN{[XluIFnDOVA:OS56IN88US=> MVuxPVEyPTh2NR?=
human SF539 cells M2SwcHBzd2yrZnXyZZRqd25iYYPzZZk> NXi2XolzPzJiaB?= MnLZRY51cXC{b3zp[oVz[XSrdnWgZYN1cX[rdImgZYdicW6|dDDoeY1idiCVRkWzPUBk\WyuczDlfJBz\XO|aX7nJJA2OyCpZX7lJIFnfGW{IEeyJIhzeyCkeTDwdo9tcW[ncnH0bZZmKGG|c3H5MEBKSzVyPUKuN|Qh|ryP NWPqeHVvOTh2Nkm4NFk>
human SW480 cells M{H2OXBzd2yrZnXyZZRqd25iYYPzZZk> MYm3NkBp MWPBcpRqeHKxbHnm[ZJifGm4ZTDhZ5Rqfmm2eTDh[4FqdnO2IIC1N{Bl\W[rY3nlcpQhcHWvYX6gV3c1QDBiY3XscJMh[W[2ZYKgO|IhcHK|IHL5JJBzd2yrZnXyZZRqfmViYYPzZZktKEmFNUC9Nk43PyEQvF2= M1HqUlE5PDZ7OEC5
human NCI60 cells M{DoRnBzd2yrZnXyZZRqd25iYYPzZZk> NH;kTYFCdnSrcILvcIln\XKjdHn2[UBi[3Srdnn0fUBi\2GrboP0JIh2dWGwIF7DTVYxKGOnbHzzMEBKSzVyPUOuNUDPxE1? M3X6blE5PDZ7OEC5
human Jurkat cells NWHMN3BUWHKxbHnm[ZJifGmxbjDhd5NigQ>? NGTw[nc4OiCq Mn7aRY51cXC{b3zp[oVz[XSrdnWgZYN1cX[rdImgZYdicW6|dDDwOVMh\GWoaXPp[Y51KGi3bXHuJGp2emujdDDj[YxteyCjZoTldkA4OiCqcoOgZpkheHKxbHnm[ZJifGm4ZTDhd5NigSxiSVO1NF0{NjJizszN NYHU[W9rOTh2Nkm4NFk>
human HCT15 cells MonkVJJwdGmoZYLheIlwdiCjc4PhfS=> M3fOOlczKGh? MkC4RY51cXC{b3zp[oVz[XSrdnWgZYN1cX[rdImgZYdicW6|dDDoeY1idiCKQ2SxOUBk\WyuczDlfJBz\XO|aX7nJJA2OyCpZX7lJIFnfGW{IEeyJIhzeyCkeTDwdo9tcW[ncnH0bZZmKGG|c3H5MEBKSzVyPUOuPFEh|ryP MVWxPFQ3QThyOR?=
human OPM2 cells MkT1VJJwdGmoZYLheIlwdiCjc4PhfS=> NUjDPWRwPzJiaB?= Mnz5RY51cXC{b3zp[oVz[XSrdnWgZYN1cX[rdImgZYdicW6|dDDoeY1idiCRUF2yJINmdGy|IHHmeIVzKDd{IHjyd{BjgSCudXPp[oVz[XOnIHLhd4VlKGG|c3H5MEBKSzVyPUSuOUDPxE1? MoPqNVkyOTV6NEW=
human HT-29 cells NGXhN5FRem:uaX\ldoF1cW:wIHHzd4F6 M4jmZVczKGh? NFXMfXhCdnSrcILvcIln\XKjdHn2[UBi[3Srdnn0fUBi\2GrboP0JIh2dWGwIFjUMVI6KGOnbHzzJIFnfGW{IEeyJIhzeyCkeTDseYNq\mW{YYPlJIJie2WmIHHzd4F6NCCLQ{WwQVUh|ryP MlLCNVkyOTV6NEW=
human K562 cells MmTNVJJwdGmoZYLheIlwdiCjc4PhfS=> MlXmO|IhcA>? M4XUTmFvfGmycn;sbYZmemG2aY\lJIFkfGm4aYT5JIFo[Wmwc4SgdFU{KGSnZnnjbYVvfCCqdX3hckBMPTZ{IHPlcIx{KGGodHXyJFczKGi{czygTWM2OD13Lki3JO69VQ>? MUOxPFQ3QThyOR?=
U937 cells MVrGeY5kfGmxbjDhd5NigQ>? M2rVUGlvcGmkaYTpc44hd2ZiVF7GZYxxcGFicILv[JVkfGmxbjDpckBWQTN5IHPlcIx{NCCLQ{WwQVE6KM7:TR?= Mn;QNVc1QDByNkS=
human HeLa cells MWTGeY5kfGmxbjDhd5NigQ>? M1zGWVUh|ryP MkLLNlQhcA>? NUXrbGtbUW6mdXP0bY9vKG:oIHHwc5B1d3OrczDpckBpfW2jbjDI[WxiKGOnbHzzJIF{e2W|c3XkJIF{KGGycHXhdoFv[2Vib3[gVGFTWCCjdDC1JJVOKGGodHXyJFI1KGi{cx?= MVqxPFQ3QThyOR?=
NHDF NVHwdGFTTnWwY4Tpc44h[XO|YYm= MVW1JO69VQ>? Mo\xNVYhcA>? MlHGTY5lfWO2aX;uJI9nKGOnbHygZ5lkdGViYYLy[ZN1KGmwIITofY1q\GmwZTDk[YZq[2mnboSgUmhFTiCjc4Pld5Nm\CCjczDEUmEhe3mwdHjld4l{KGmwIGOtdIhie2ViYYSgOUB2VSCjZoTldkAyPmi{czDGRWNUKGGwYXz5d4l{KGmwIIDy[ZNmdmOnIH;mJJNmenWv NXT2bYE5OTh2Nkm4NFk>

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Western blot
p-MCM2 / CDC7 ; 

PubMed: 24902048     


HeLa cells were treated with PHA-767491 for the indicated time. Protein extracts were prepared and analysed by western blot with the indicated antibodies.

RNA Pol II / p-RNA Pol II / Caspase-3 / PARP / Mcl-1 / XIAP / Bcl-xL / Bcl-2 / NOXA; 

PubMed: 24202326     


KMS-18 and MM1S myeloma cells were incubated with 5 μM PHA-767491 for the indicated time. Protein extracts were prepared and analyzed by immunoblotting using the indicated antibodies

24902048 24202326
In vivo Administration of PHA-767491 twice a day for 5 days significantly inhibits the growth of HL60 xenograft in a dose-dependent manner with TGI of 50% and 92% at dose of 20 mg/kg and 30 mg/kg, respectively, the effect of which is also marked in A2780, Mx-1, and HCT-116 xenograft models as well as the DMBA-induced mammary carcinomas, and correlates with Cdc7 inhibition and subsequently decreased phosphorylation of Mcm2 at the Cdc7-dependent site Ser40 [1]

Protocol

Kinase Assay:[1]
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In vitro kinase assays:

The inhibition of Cdc7 and Cdk9 by PHA-767491 (IC50) is determined using the strong anion exchanger (Dowex 1-X8 resin, formate form)-based assay. For each enzyme, the absolute Km values for ATP and the specific substrate are initially determined, and each assay is then run at optimized ATP/33P-γ-ATP mix (2Km) and substrate (5Km) concentrations. Cdc7 kinase assay is performed in a buffer containing 50 mM Hepes pH 7.9, 15 mM MgCl2, 2 mM β- glycerylphosphate, 0.2 mg/mL BSA, 1 mM DTT, 3 μM Na3VO4, 2Km ATP/33P-γ-ATP mix, 5Km Mcm2 (aa 10-294), 37 nM of recombinant Cdc7/Dbf4 and increasing concentration of PHA-767491 in a final volume of 30 μL, and incubated for 1 hour at 25 °C. Cdk9 kinase assay is performed using 50 nM of recombinant Cdk9/cyclin T in 50 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM DTT, 3 μM Na3VO4, 2Km ATP/33P-γ-ATP mix, 5Km RNA polymerase CDT peptide and increasing concentration of PHA-767491 in a final volume of 30 μL, and incubated for 1 hour at 25 °C. After incubation, an amount of 150 μL of resin/formate (pH 3.0) is added to stop the reaction and capture unreacted 33P-γ-ATP, separating it from the phosphorylated substrate in solution. After 1 hour of rest, a volume of 50 μL supernatant is transferred to Optiplate 96-well plates. After the additon of 150 μL of Microscint 40, the radioactivity is counted in the TopCount.
Cell Research:[1]
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  • Cell lines: HeLa, MCF7, HCT-116, U2OS, A2780, K562, SF-539, SF-268, Ovcar8, SW480, COLO205, HCT-15, Jurkat, PC3, and NHDF
  • Concentrations: Dissolved in DMSO, final concentrations ~ 20 μM
  • Incubation Time: 24 or 72 hours
  • Method: Cells are exposed to PHA-767491 for 24 or 72 hours. Cells are lysed and the ATP content in the well, used as a measure of viable cells, is determined using a thermostable firefly luciferase–based assay. Activation of caspase-3 and caspase-7 is measured as a ratio between treated sample and untreated control with a luciferase-based assay, containing a specific proluminescent substrate. DNA replication is measured as incorporation of nucleotide analog BrdU into DNA by flow cytometry.
    (Only for Reference)
Animal Research:[1]
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  • Animal Models: Female SCID mice subcutaneously implanted with HL60 cells, male Hsd, athymic nu-nu mice subcutaneously implanted with HCT116 cells, A2780 or Mx-1 cells, and female Sprague-Dawley rats with DMBA-induced mammary carcinomas
  • Dosages: ~50 mg/kg
  • Administration: Intravenous or oral administration twice a day
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 24 mg/mL (96.11 mM)
Water Insoluble
Ethanol Insoluble
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
5% DMSO+30% PEG 300+2% Tween 80+ddH2O
For best results, use promptly after mixing.
1mg/mL

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 249.7
Formula

C12H11N3O.HCl

CAS No. 942425-68-5
Storage powder
in solvent
Synonyms CAY10572, NMS 1116354
Smiles C1CNC(=O)C2=C1NC(=C2)C3=CC=NC=C3.Cl

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID