XL019 (XL-019) is a novel, potent and selective and orally bioavailable inhibitor of Janus kinase-JAK2 with potential antitumor activity. It inhibits JAK2 with an IC50 of 2.2 nM, and exhibits >50-fold selectivity for JAK2 over JAK1, JAK3 and TYK2. It shows potent in vitro antiproliferative activity and high in vivo antitumor efficacy. XL019 inhibits the activation of JAK2 as well as the mutated form JAK2V617F, which may result in the inhibition of the JAK-STAT signaling pathway and may induce apoptosis. The JAK2 mutated form JAK2V617F has a valine-to-phenylalanine modification at position 617 and plays a key role in tumor cell proliferation and survival.
Physicochemical Properties
| Molecular Formula | C25H28N6O2 | |
| Molecular Weight | 444.53 | |
| Exact Mass | 444.227 | |
| CAS # | 945755-56-6 | |
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| PubChem CID | 57990869 | |
| Appearance | Green to yellow solid powder | |
| Density | 1.3±0.1 g/cm3 | |
| Index of Refraction | 1.662 | |
| LogP | 1.71 | |
| Hydrogen Bond Donor Count | 3 | |
| Hydrogen Bond Acceptor Count | 7 | |
| Rotatable Bond Count | 6 | |
| Heavy Atom Count | 33 | |
| Complexity | 614 | |
| Defined Atom Stereocenter Count | 1 | |
| SMILES | C1C[C@H](NC1)C(=O)NC2=CC=C(C=C2)C3=NC(=NC=C3)NC4=CC=C(C=C4)N5CCOCC5 |
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| InChi Key | ISOCDPQFIXDIMS-QHCPKHFHSA-N | |
| InChi Code | InChI=1S/C25H28N6O2/c32-24(23-2-1-12-26-23)28-19-5-3-18(4-6-19)22-11-13-27-25(30-22)29-20-7-9-21(10-8-20)31-14-16-33-17-15-31/h3-11,13,23,26H,1-2,12,14-17H2,(H,28,32)(H,27,29,30)/t23-/m0/s1 | |
| Chemical Name | (S)-N-(4-(2-((4-morpholinophenyl)amino)pyrimidin-4-yl)phenyl)pyrrolidine-2-carboxamide | |
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| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vitro |
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| ln Vivo | XL019 (po; twice daily for 14 days; 100–300 mg/kg) suppresses the formation of HEL.92.1.7 xenograft tumors[1]. The Cmax, t1/2, and Vd for XL019 (10 mg/kg) dosing were 5.24 μM, 1.94 hours, and 5.319 L/kg, respectively[1]. | |
| Animal Protocol |
Animal/Disease Models: Female nude mice (HEL.92.1.7 xenograft tumors)[1] Doses: 100, 200, 300 mg/kg Route of Administration: po; twice (two times) daily for 14 days Experimental Results: Inhibition of HEL.92.1.7 xenograft tumor growth. Animal/Disease Models: Mouse[1] Doses: 10 mg/kg Route of Administration: po(pharmacokinetic/PK Analysis) Experimental Results: The Cmax, t1/2 and Vd were 5.24 μM, 1.94 hrs (hours), and 5.319 L/kg, respectively. |
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| References |
[1]. SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors. Bioorg Med Chem Lett. 2012 Dec 15;22(24):7653-8. |
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| Additional Infomation |
XL019 is a selective inhibitor of the cytoplasmic tyrosine kinase JAK2. An IND for XL019 was filed by Exelixis in May 2007. JAK2 Inhibitor XL019 is an orally bioavailable inhibitor of Janus-associated kinase 2 (JAK2) with potential antineoplastic activity. XL019 inhibits the activation of JAK2 as well as the mutated form JAK2V617F, which may result in the inhibition of the JAK-STAT signaling pathway and may induce apoptosis. The JAK2 mutated form JAK2V617F has a valine-to-phenylalanine modification at position 617 and plays a key role in tumor cell proliferation and survival. Drug Indication For the treatment of various forms of cancer. Mechanism of Action XL019 is a selective inhibitor of the cytoplasmic tyrosine kinase JAK2. JAK2 is activated by cytokine and growth factor receptors and phosphorylates members of the STAT family of inducible transcription factors. Activation of the JAK/STAT pathway promotes cell growth and survival, and is a common feature of human tumors. JAK2 is activated by mutation in the majority of patients with polycythemia vera and essential thrombocytosis and appears to drive the inappropriate growth of blood cells in these conditions. Pharmacodynamics XL019 is a potent and selective JAK2 inhibitor with favorable pharmacodynamic properties and safety profile. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.62 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 + to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2496 mL | 11.2478 mL | 22.4957 mL | |
| 5 mM | 0.4499 mL | 2.2496 mL | 4.4991 mL | |
| 10 mM | 0.2250 mL | 1.1248 mL | 2.2496 mL |