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Purity: =98.89%
PRN1371 is a highly selective, potent, covalent, and irreversible FGFR1,2,3,4 inhibitor with IC50 values of 0.6, 1.3, 4.1 and 19.3 nM, respectively. PRN1371 exhibited a unique profile of high biochemical and cellular potency (FGFR1 IC50 = 0.6 nM, SNU16 IC50 = 2.6 nM), prolonged target engagement (FGFR1 occupancy 24 h = 96%),<30% 1='' herg='' inhibition='' at='' and='' good='' predicted='' adme='' stability='' with='' bme='' reactivity='' kd=''>100 μM. PRN1371 which maintained high FGFR1 occupancy with improved solubility and exceptional oral bioavailability. Because of the broad spectrum of activity against FGFR1-4, it has the potential to treat many tumor types, including urothelial, squamous lung, gastric and hepatocellular carcinoma.
| Targets |
FGFR1 (IC50 = 0.6 nM); FGFR2 (IC50 = 1.3 nM); FGFR3 (IC50 = 4.1 nM); FGFR4 (IC50 = 19.3 nM); CSF1R (IC50 = 8.1 nM)
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| ln Vitro |
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| Enzyme Assay |
Using a Caliper capillary electrophoresis system that divides phosphorylated and nonphosphorylated peptides according to charge, enzyme inhibition is measured. Initially, PRN1371 is preincubated with the enzyme for 15 minutes at varying concentrations. The peptide substrate, ATP, and Mg2+ are added to start the reaction, which is then incubated for three hours at 25°C. EDTA is used to quench the mixture in order to stop the reaction. pH 7.5, 100 mM HEPES, 0.1% BSA, 0.01% Triton X-100, 1 mM DTT, 10 mM MgCl2, 10 mM sodium orthovanadate, 10 μM β-glycerophosphate, and 1% DMSO make up the buffer. The reaction's ATP concentration is at the predefined ATP Km value[1].
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| Cell Assay |
To achieve a final compound concentration of 5 μM, SNU16 cells are first seeded into 384-well plates and then PRN1371 is added. PRN1371, at 37°C, is incubated for 72 hours in cells. The Presto-Blue cell viability reagent is added to the sample in order to determine status. Using 530 nm excitation and 590 nm emission in the fluorescent mode, the Analyst HT is used to read plates[1].
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| Animal Protocol |
Mice: Using a SNU16 gastric cancer xenograft mouse model with high FGFR2 overexpression, PRN1371 is assessed in pharmacodynamic and efficacy studies. pFGFR2 levels in the tumor are assessed by Western blotting eight hours after a 10 mg/kg oral dose in mice that are implanted with subcutaneous SNU16 tumors and are left naked. Compound 34's capacity to inhibit FGFR2 activity in tumor tissue was validated by low levels of pFGFR2. Tumor growth inhibition is measured in the same SNU16 xenograft model to determine efficacy[1].
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| References |
| Molecular Formula |
C26H30CL2N6O4
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| Molecular Weight |
561.46
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| Exact Mass |
560.17
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| Elemental Analysis |
C, 55.62; H, 5.39; Cl, 12.63; N, 14.97; O, 11.40
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| CAS # |
1802929-43-6
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| Related CAS # |
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| Appearance |
Solid powder
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| SMILES |
CNC1=NC=C2C=C(C(=O)N(C2=N1)CCCN3CCN(CC3)C(=O)C=C)C4=C(C(=CC(=C4Cl)OC)OC)Cl
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| InChi Key |
PUIXMSRTTHLNKI-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C26H30Cl2N6O4/c1-5-20(35)33-11-9-32(10-12-33)7-6-8-34-24-16(15-30-26(29-2)31-24)13-17(25(34)36)21-22(27)18(37-3)14-19(38-4)23(21)28/h5,13-15H,1,6-12H2,2-4H3,(H,29,30,31)
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| Chemical Name |
6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-8-[3-(4-prop-2-enoylpiperazin-1-yl)propyl]pyrido[2,3-d]pyrimidin-7-one
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| Synonyms |
PRN-1371; PRN 1371; PRN1371
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.45 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 (4.45 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. 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 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.45 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7811 mL | 8.9054 mL | 17.8107 mL | |
| 5 mM | 0.3562 mL | 1.7811 mL | 3.5621 mL | |
| 10 mM | 0.1781 mL | 0.8905 mL | 1.7811 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02608125 | Terminated | Drug: PRN1371 | Metastatic Urothelial Carcinoma & Renal Pelvis & Ureter Solid Tumors |
Principia Biopharma, a Sanofi Company |
October 28, 2015 | Phase 1 |
Rat in vivo inhibition of bFGF-induced CCL2 production.J Med Chem.2017 Aug 10;60(15):6516-6527. |
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PK/PD and efficacy of compound34in a SNU16 mouse xenograft model.J Med Chem.2017 Aug 10;60(15):6516-6527. |
Phase I clinical data for once daily oral administration of compound34.J Med Chem.2017 Aug 10;60(15):6516-6527. |
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