XL019

Cell lines

HEL92.1.7 and KG-1 tumor cell lines, primary human erythroid cells

Preparation method

The solubility of this compound in DMSO is > 11.1 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

24h

Applications

XL019 downregulated STAT signaling in cell lines expressing both wild type and activated forms of JAK2. IC50s for inhibition of STAT5 phosphorylation by XL019 ranged from 623 nM (HEL92.1.7) to 3398 nM (KG-1) in tumor cell lines. XL019 showed increased potency in primary human erythroid cells, where the IC50 for inhibition of EPO-stimulated phospho-STAT5 was 64 nM. XL019 inhibited proliferation in cell lines harboring activated or overexpressed JAK2, including certain lines derived from patients with Hodgkin’s Lymphoma (L-1236, 928 nM IC50), AML (MV4-11, 992 nM IC50), essential thrombocythemia (SET-2, 386 nM IC50), and erythroleukemia (HEL92.1.7, 6777 nM IC50).

Animal models

Mice bearing HEL92.1.7, CFPAC-1 and DU 145 xenograft tumors

Dosage form

Oral administration, 30, 100, and 300 mg/kg.

Application

Oral administration of XL019 (30, 100, and 300 mg/kg) significantly inhibited downstream markers pSTAT1 and pSTAT3 with an ED50 of 42 mg/kg (pSTAT1) and 210 mg/kg (pSTAT3). XL019 demonstrated 60% and 70% inhibition when dosed orally at 200 mg/kg and 300 mg/kg respectively twice a day for 14 days. XL019 showed a superior pharmacodynamic profile and exhibited good oral absorption, and modest clearance and halflife across species. XL019 inhibited HEL.92.1.7 xenograft tumors growth in mice. XL019 showed potent effect on JAK-STAT signaling in HEL92.1.7, CFPAC-1 and DU 145 xenograft tumors. Twice daily dosing (bid) led to substantial tumor growth inhibition in the DU145 and HEL models (maximum tumor growth inhibition of 86% and 60%, respectively), accompanied by increases in tumor cell apoptosis (4 – 4.4 fold increase) and decreases in tumor microvasculature (44% reduction in DU 145 xenograft tumors).

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1]. Verstovsek S, Pardanani A D, Shah N P, et al. A Phase I Study of XL019, a Selective JAK2 Inhibitor, in Patients with Primary Myelofibrosis and Post-Polycythemia Vera/Essential Thrombocythemia Myelofibrosis[J]. 2007.

[2]. Forsyth T, Kearney P C, Kim B G, et al. SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors[J]. Bioorganic & medicinal chemistry letters, 2012, 22(24): 7653-7658.