PRN1371

Catalog No.S8578

PRN1371 Chemical Structure

Molecular Weight(MW): 561.46

PRN1371 is an irreversible covalent FGFR1-4 kinase inhibitor, with IC50s of 0.6, 1.3, 4.1, 19.3 and 8.1 nM for FGFR1, 2, 3, 4 and CSF1R, respectively.

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Biological Activity

Description PRN1371 is an irreversible covalent FGFR1-4 kinase inhibitor, with IC50s of 0.6, 1.3, 4.1, 19.3 and 8.1 nM for FGFR1, 2, 3, 4 and CSF1R, respectively.
Targets
FGFR1 [1]
(Cell-free assay)		 FGFR2 [1]
(Cell-free assay)		 FGFR3 [1]
(Cell-free assay)		 CSF1R [1]
(Cell-free assay)		 FGFR4 [1]
(Cell-free assay)
0.6 nM 1.3 nM 4.1 nM 8.1 nM 19.3 nM
In vitro

PRN1371 is an irreversible nanomolar inhibitor of FGFR1−4. PRN1371 presents 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% hERG inhibition at 1 μM, and good predicted ADME stability with BME reactivity Kd>100 μM. PRN1371 which maintained high FGFR1 occupancy with improved solubility and exceptional oral bioavailability[1].
Assay
Methods Test Index PMID
Western blot
p-STAT5 / STAT5 / p-STAT3 / STAT3; 

PubMed: 29434279     


The effect of PRN371 on the downstream effector proteins of the JAK3-STAT pathway in JAK3-dependent cells. Cells were treated with the indicated concentration for 2 h.

29434279
Growth inhibition assay
Cell viability; 

PubMed: 29434279     


Dose-dependent response of JAK3-driven cells to PRN371 treatment. Cells were treated with the indicated concentration for 96 h. Cell viability is normalized to the control (DMSO) and presented as mean ± s.d. 

29434279
In vivo A rat iv (2 mg/kg) PK study of compound 34 showed rapid clearance (Cl = 160 ml/min/kg), yet dosing po (20 mg/kg) demonstrated high oral exposure (AUC = 4348 h·ng/mL) and a reasonable half-life (t1/2 = 3.8 h). PK studies of compound 34 in rat, dog, and cynomolgus monkey showed rapid iv clearance in all species; however there were large species differences in oral exposure and bioavailability for monkey compared to rat and dog. In rat, high exposure upon oral dosing (e.g., Cmax = 1785 ng/mL, AUC = 4348 ng·h/mL) and >100% bioavailability (F) suggested good absorption and partial saturation of clearance mechanisms at the 20 mg/kg dose. Unique to the rat, there is a large difference in half-life between the iv (t1/2 = 0.8 h) and po (t1/2 = 3.8 h) routes of administration, also indicative of possible saturation of a clearance mechanism upon oral dosing. In the dogs, the same methylcellulose suspension formulation used for the rat gave low oral absorption and bioavailability (F < 15%). In SNU16 gastric cancer xenograft mouse model, Compound 34 induced a dose-dependent reduction in tumor volume and up to 68% tumor growth inhibition at the highest dose of 10 mg/kg b.i.d. following 27 days of treatment. All doses were well tolerated with no significant body weight loss[1].

Protocol

Cell Research:

[1]
+ Expand
  • Cell lines: HUVECs
  • Concentrations: --
  • Incubation Time: 1 h
  • Method:

    Human umbilical vein endothelial cells (HUVECs) were incubated in media supplemented with 10% FBS and seeded at 30 000 cells per well in a 96-well plate overnight. HUVECs were then transferred into serum free media 1 h before compound treatment. A compound concentration series was added to cells and incubated for 1 h at 37 °C. Cells were then stimulated with either 50 ng/mL of FGF2 or 50 ng/mL of VEGF for 10 min. Ice cold PBS was added to stop the reaction, and cells were washed three times to remove media. ERK phosphorylation is determined.


    (Only for Reference)
Animal Research:

[1]
+ Expand
  • Animal Models: SNU16 gastric cancer xenograft mouse model
  • Formulation: 0.5% methylcellulose w/w in deionized water
  • Dosages: 10 mg/kg
  • Administration: oral
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 100 mg/mL (178.1 mM)
Ethanol 6 mg/mL (10.68 mM)
Water Insoluble

* 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 561.46
Formula

C26H30Cl2N6O4
CAS No. 1802929-43-6
Storage powder
in solvent
Synonyms N/A

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID