PRN1371

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.

Product information

CAS Number: 1802929-43-6

Molecular Weight: 561.46

Formula: C26H30Cl2N6O4

Chemical Name: 6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-8-{3-[4-(prop-2-enoyl)piperazin-1-yl]propyl}-7H,8H-pyrido[2,3-d]pyrimidin-7-one

Smiles: CNC1N=C2C(C=C(C3C(Cl)=C(C=C(OC)C=3Cl)OC)C(=O)N2CCCN2CCN(CC2)C(=O)C=C)=CN=1

InChiKey: PUIXMSRTTHLNKI-UHFFFAOYSA-N

InChi: 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)

Technical Data

Appearance: Solid Power

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: Solubility (25°C). 100 mg/mL(178.1 mM). Insoluble.

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined

HS Tariff Code: 382200

How to use

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.

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.

Products are for research use only. Not for human use.