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PRN1371

Catalog No.S8578

For research use only.

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.

CAS No. 1802929-43-6

Selleck's PRN1371 has been cited by 1 Publication

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FGFR Signaling Pathway Map

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	29434279
Growth inhibition assay	Cell viability	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 (from reference)

Cell Research: ^[1]	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.
Animal Research: [1]	Animal Models: SNU16 gastric cancer xenograft mouse model Dosages: 10 mg/kg Administration: oral

Cell Research:

^[1]

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.

Animal Research:

[1]

Animal Models: SNU16 gastric cancer xenograft mouse model
Dosages: 10 mg/kg
Administration: oral

References	[1] Brameld KA, et al. J Med Chem. 2017, 60(15):6516-6527.

References

[1] Brameld KA, et al. J Med Chem. 2017, 60(15):6516-6527.

Solubility (25°C)

In vitro

Chemical Information

Molecular Weight	561.46
Formula	C₂₆H₃₀Cl₂N₆O₄
CAS No.	1802929-43-6
Storage	3 years	-20°C	powder
Storage	2 years	-80°C	in solvent
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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In vivo Formulation Calculator (Clear solution)

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Clinical Trial Information

NCT Number	Recruitment	Interventions	Conditions	Sponsor/Collaborators	Start Date	Phases
NCT02608125	Terminated	Drug: PRN1371	Solid Tumors\|Metastatic Urothelial Carcinoma & Renal Pelvis & Ureter	Principia Biopharma a Sanofi Company	October 28 2015	Phase 1

(data from https://clinicaltrials.gov, updated on 2022-01-17)

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