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Purity: ≥98%
1-NM-PP1, a C3-modified analog of PP1, is a novel, potent and cell permeable protein kinase D (PKD) inhibitor with an IC50 of 0.398 μM. 1-NM-PP1 has shown the selective inhibition of protein kinases that have been mutated with the IC50 values of 28 μM, 1.0 μM, 3.4 μM, 29 μM, 24 μM,4.3 nM, 3.2 nM, 120 nM,5 nM and 8 nM for v-Src, c-Fyn, c-Abl, CDK2, CAMKII, v-Src-as1, c-Fyn-as1, cAbl-as2, CDK2-as1 and CAMKII-as1, respectively. In comparison to the most inhibitable wild-type kinases, 1-NM-PP1 inhibited all five target kinases at low nanomolar concentrations, with target-specificities ranging from 85- to 400-fold. Cdc28-as1 is also very sensitive to 1-NM-PP1, according to the in vitro study, which also showed that Cdc28/Clb2 and Cdc28-as1/Clb2 had IC50 values of 22 μM and 0.002 μM, respectively, and ATP kinetic Km values of 35 μM and 322 μM, Kcat values of 132 min-1 and 21.3 min-1, and Kcat/Km values of 3.7 and 0.066.
| Targets |
VEGFR1 (IC50 = 4.3 nM); c-Fyn-as1 (IC50 = 3.2 nM); v-Src (IC50 = 28 μM); c-Fyn (IC50 = 1 μM); c-Abl (IC50 = 3.4 μM); CDK2 (IC50 = 29 μM); CAMKII (IC50 = 24 μM); cAbl-as2 (IC50 = 120 nM); CDK2-as1 (IC50 = 5 nM); CAMKII-as1 (IC50 = 8 nM)
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| ln Vitro |
Cdk7 from Cdk7as/as or Cdk7+/+ cells is immunoprecipitated, and its kinase activity is assessed against human Cdk2 and a Pol II CTD-containing fusion protein (GST-CTD). With an IC50 of ~50 nM for either substrate, 1-NM-PP1 (1-NMPP1) inhibits Cdk7 that is recovered from the mutant cells but not from the wild-type cells. The growth of HCT116 cells became sensitive to 1-NM-PP1 when Cdk7as/as was substituted for wild-type Cdk7. The wild-type and Cdk7as/as cells had population doubling times of approximately 17.9 and 20.2 hours, respectively, in the absence of 1-NM-PP1, with similar cell-cycle distributions in asynchronous culture, suggesting a minimal impairment of Cdk7 function per se by the F91G mutation. The homozygous Cdk7as/as cells exhibit sensitivity to 1-NM-PP1, as demonstrated by cell viability (MTT) assays conducted 96 hours after 1-NM-PP1 exposure, revealing an IC50 of approximately 100 nM. Wild-type HCT116 cells, on the other hand, are resistant to 10 μM 1-NM-PP1. When 10 μM 1-NM-PP1 is added, the mutant cells' G1/S progression is retarded, but not that of the wild-type cells. When 1-NM-PP1 is added to the Cdk7as/as cells concurrently with serum, it stops the cells from entering S phase for the next fifteen hours. A portion of Cdk7as/as cells released from serum starvation and placed straight into medium containing 1-NM-PP1 showed evidence of progressing into S-phase after 24 hours, whereas a portion of the cells stayed in G1. 1-NM-PP1 is added either 3 or 6 hours after serum addition, which causes a ~7- or ~3-hour delay in S-phase entry[3].
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| Enzyme Assay |
Assays for kinase of immune complexes, immunoblotting, and immunoprecipitation are performed. A system for regenerating ATP is added, along with 500 ng of purified cyclin B1, which is amino-terminally tagged with hexahistidine and the Myc epitope, to extracts (200 μg total protein) from cells in mitosis or G2. This pre-incubation is done with 2 μM 1-NM-PP1 or DMSO. When indicated, 400 ng of purified Csk1 or 600 ng of the wild-type or analog-sensitive, T-loop-phosphorylated Cdk7/cyclin H/Mat1 complex are added to the incubations. The process involves letting Myc-cyclin B and related proteins sit at room temperature for 90 minutes. Then, immune complexes are immunoprecipitated using anti-Myc and anti-Cdk1 antibodies, and their histone H1 kinase activity is assessed[3].
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| Cell Assay |
After 48 hours of incubation in serum-free medium, wild-type or Cdk7as/as HCT116 cells are synchronized and released into medium containing 10% fetal calf serum. Cell-cycle distribution is analyzed using flow cytometry, and thymidine or nocodazole synchronization is carried out. The MTT assay is used to determine cell viability[3].
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| References |
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| Additional Infomation |
1-NM-PP1 is a pyrazolopyrimidine. It has a role as a tyrosine kinase inhibitor.
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| Molecular Formula |
C20H21N5
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| Molecular Weight |
331.4142
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| Exact Mass |
331.179
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| Elemental Analysis |
C, 72.48; H, 6.39; N, 21.13
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| CAS # |
221244-14-0
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| Related CAS # |
221244-14-0
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| PubChem CID |
5154691
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| Appearance |
white solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
545.7±45.0 °C at 760 mmHg
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| Melting Point |
175-176ºC
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| Flash Point |
283.8±28.7 °C
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| Vapour Pressure |
0.0±1.5 mmHg at 25°C
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| Index of Refraction |
1.675
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| LogP |
3.96
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
25
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| Complexity |
462
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| Defined Atom Stereocenter Count |
0
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| SMILES |
N1(C2C(=C(N([H])[H])N=C([H])N=2)C(C([H])([H])C2=C([H])C([H])=C([H])C3=C([H])C([H])=C([H])C([H])=C23)=N1)C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H]
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| InChi Key |
GDQXJQSQYMMKRA-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H21N5/c1-20(2,3)25-19-17(18(21)22-12-23-19)16(24-25)11-14-9-6-8-13-7-4-5-10-15(13)14/h4-10,12H,11H2,1-3H3,(H2,21,22,23)
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| Chemical Name |
1-tert-butyl-3-(naphthalen-1-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-amine
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| Synonyms |
1NM PP1; 1NM-PP1; 1NMPP1l PP1 analog II
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~27.5 mg/mL (~82.9 mM）
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.54 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (7.54 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.0174 mL | 15.0871 mL | 30.1741 mL | |
| 5 mM | 0.6035 mL | 3.0174 mL | 6.0348 mL | |
| 10 mM | 0.3017 mL | 1.5087 mL | 3.0174 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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