An orally available inhibitor of ALK and ROS1
PF-06463922 is a potent and selective ALK/ROS1 inhibitor with IC50 values ranging from 0.19-0.53 nM for the kinase activity of ROS1 fusion enzymes [1].
The receptor tyrosine kinase c-ros oncogene1 (ROS1) is a receptor with a kinase domain that is related to the anaplastic lymphoma kinase/lymphocyte-specific protein tyrosine kinase (ALK/LTK) and insulin receptor (INSR) RTK families [1].
Via cellular ROS1 autophosphorylation in the recombinant enzyme assay, PF-06463922 showed a 30-fold improved potency against ROS1, compared with crizotinib, ceritinib, alectinib and foretinib (XL-880). Engineered NIH 3T3 cells were expressing oncogenic human ROS1 fusions. In these cells, PF-06463922 was more potent than foretinib and crizotinib by >10 folds, more potent than alectinib and ceritinib by >100 folds against cellular ROS1 autophosphorylation [1].
Oncogenic gene fusions involving the 3' region of ROS1 kinase had been found in various human cancers [2]. Mice bearing CD74-ROS1, CD74-ROS1G2032R and FIG-ROS1(S) s.c. Tumors (250 mm3) were used. Treatments with PF-06463992 at various doses were applied consecutively for 7 or 9 d. At dosages of 0.2 to 1 mg/kg/d, PF-06463922 significantly inhibited the growth of both established FIGROS1(S) and CD74-ROS1 tumors compared with vehicle control. At 2-6 mg/kg/d, PF-06463922 significantly made tumor volumes regress (58–85%, P < 0.0001). In animals bearing NIH 3T3-CD74-ROS1G2032R tumors, treatment with PF-06463922 at 1.0, 3.0, and 10 mg/kg/d significantly inhibited tumor growth by 28%, 44% and 90%, respectively. At 30 mg/kg/d, PF-06463922 made tumor regress by 12%, compared with vehicle [1].
参考文献:
[1].? Zou HY, Li Q, Engstrom LD, et al. PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations. Proceedings of the National Academy of Sciences, 2015, 112(11): 3493-3498.
[2].? Davies KD, Le AT, Theodoro MF, et al. Identifying and targeting ROS1 gene fusions in non–small cell lung cancer. Clinical Cancer Research, 2012, 18(17): 4570-4579.
| Cell experiment [1]: | |
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Cell lines |
HCC78 cells harboring the SLC34A2-ROS1(S/L) proteins and BaF3 cells engineered to express the CD74-ROS1 fusion |
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Preparation method |
The solubility of this compound in DMSO is >20.3mg/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. |
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Reacting condition |
0-10000 nM |
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Applications |
In HCC78 and BaF3 CD74-ROS1 cells, PF-06463922 potently inhibited cell proliferation with IC50 values of 1.3 and 0.6 nM, respectively. PF-06463922 dose-dependently decreased phosphorylation of SLC34A2-ROS1 and downstream signaling molecules SHP2, Erk1/2, and AKT in HCC78 cells. |
| Animal experiment [1]: | |
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Animal models |
mice bearing FIG-ROS1 glioblastoma multiforme (GBM) tumors |
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Dosage form |
10 mg/kg/d; s.c. osmotic pumps; 3-, 7-, or 14-d treatment |
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Application |
In mice bearing FIG-ROS1 GBM tumors, PF-06463922 significantly regressed the GBM LSL-FIG-ROS1;Cdkn2a-/-;LSL-Luc tumors following a 7-d and 14-d treatment. PF-06463922 reduced overall tumor cell size and the number of Ki67-positive cells. PF-06463922 reduced pFIG-ROS1, pSHP2, pMEK1/2, and pERK1/2 in tumor cell lysates. |
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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. |
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参考文献: [1]. Zou HY, Li Q, Engstrom LD, et al. PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations. Proceedings of the National Academy of Sciences, 2015, 112(11): 3493-3498. | |
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