PRN1371

Research use only, not for human use.

PRN1371 is a specific and potent FGFR1-4 and CSF1R inhibitor (IC50s: 0.6/1.3/4.1/19.3/8.1 nM for FGFR1/2/3/4 and CSF1R).

PRN1371 is a specific and potent FGFR1-4 and CSF1R inhibitor (IC50s: 0.6/1.3/4.1/19.3/8.1 nM for FGFR1/2/3/4 and CSF1R).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.In PK studies of rat, dog, and cynomolgus monkey, PRN1371show rapid iv clearance in all species. PRN1371 shows rapid clearance (Cl=160 mL per min per kg), yet dosing p.o (20 mg/kg) demonstrates high oral exposure (AUC=4348 h·ng/mL) and a reasonable half-life (t1/2=3.8 h). Low levels of pFGFR2 confirm the ability of PRN1371 to block FGFR2 activity in tumor tissue. PRN1371 induces 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 are well tolerated with no significant bodyweight loss.(In Vitro):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. Broader kinome-wide biochemical profiling of PRN1371 against 251 kinases identifies only FGFR1?4 and CSF1R as being potently inhibited.(In Vivo):PK studies of PRN1371 in rat, dog, and cynomolgus monkey show rapid iv clearance in all species. PRN1371 shows rapid clearance (Cl=160 mL per min per kg), yet dosing po (20 mg/kg) demonstrates high oral exposure (AUC=4348 h·ng/mL) and a reasonable half-life (t1/2=3.8 h). Low levels of pFGFR2 confirms the ability of PRN1371 to block FGFR2 activity in tumor tissue. PRN1371 induces 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 are well tolerated with no significant body weight loss. PRN1371 free base has been administered orally once daily as powder in a capsule on a 28-day continuous schedule. Human plasma concentrations for doses ranging from 15 to 35 mg confirm good oral exposure, rapid systemic clearance, no accumulation from day 1 to day 15, and a dose-dependent increase in AUC. Serum phosphate, a pharmacodynamic marker of FGFR inhibition, is increased for all doses studied and shows a dose-dependent increase between 20 and 35 mg, despite the administration of prophylactic phosphate binders.

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. Broader kinome-wide biochemical profiling of PRN1371 against 251 kinases identifies only FGFR1?4 and CSF1R as being potently inhibited.

PK studies of PRN1371 in rat, dog, and cynomolgus monkey show rapid iv clearance in all species. PRN1371 shows rapid clearance (Cl=160 mL per min per kg), yet dosing po (20 mg/kg) demonstrates high oral exposure (AUC=4348 h·ng/mL) and a reasonable half-life (t1/2=3.8 h). Low levels of pFGFR2 confirms the ability of PRN1371 to block FGFR2 activity in tumor tissue. PRN1371 induces 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 are well tolerated with no significant body weight loss. PRN1371 free base has been administered orally once daily as powder in a capsule on a 28-day continuous schedule. Human plasma concentrations for doses ranging from 15 to 35 mg confirm good oral exposure, rapid systemic clearance, no accumulation from day 1 to day 15, and a dose-dependent increase in AUC. Serum phosphate, a pharmacodynamic marker of FGFR inhibition, is increased for all doses studied and shows a dose-dependent increase between 20 and 35 mg, despite the administration of prophylactic phosphate binders.

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Angiogenesis

FGFR

FGFR1| FGFR2| FGFR3| FGFR4| CSF-1R

Cancer

Solid tumours; Urogenital cancer

1802929-43-6

561.46

C26H30Cl2N6O4

>98% (HPLC)

DMSO:12 mg/mL (21.38 mM; Need ultrasonic and warming)

CNc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)c(=O)n(CCCN3CCN(CC3)C(=O)C=C)c2n1

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(-20℃)

With Ice Pack

≥ 2 years