Table 1.
Clinically approved TKIs with anti-RET inhibitory activity
| Compound | Other names | 1IUPAC name | 2Targets (IC50 nM) | References |
|---|---|---|---|---|
|
| ||||
| Vandetanib | Zactima; ZD6474 | N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine | VEGFR2 (40) | Herbst et al. 2007 |
| VEGFR3 (110) | ||||
| RET (130) | ||||
| EGFR (500) | ||||
|
| ||||
| Cabozantinib | BMS-907351; XL-184 | 1-N-[4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide | VEGFR2 (0.035) | Yakes et al. 2011 |
| MET (1.3) | ||||
| KIT (4.6) | ||||
| RET (5.2) | ||||
| AXL (7) | ||||
| FLT3 (11.3) | ||||
| TIE2 (14.3) | ||||
| RON (124) | ||||
|
| ||||
| Lenvatinib | Lenvima; E7080; | 4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxyquinoline-6-carboxamide | RET (1.5) | Okamoto et al. 2013 |
| VEGFR2 (4) | Matsui et al. 2008 | |||
| VEGFR3 (5.2) | Matsui et al. 2008 | |||
| VEGFR1 (22) | Matsui et al. 2008 | |||
| PDGFRβ (39) | Matsui et al. 2008 | |||
| FGFR1 (46) | Matsui et al. 2008 | |||
| PDGFRα (51) | Matsui et al. 2008 | |||
| KIT (100) | Matsui et al. 2008 | |||
|
| ||||
| Ponatinib | Iclusig; AP24534 | 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide | LYN (0.24) | O'Hare et al. 2009 |
| ABL (0.37) | O'Hare et al. 2009 | |||
| PDGFRα (1.1) | O'Hare et al. 2009 | |||
| VEGFR2 (1.5) | O'Hare et al. 2009 | |||
| FGFR1 (2.2) | O'Hare et al. 2009 | |||
| SRC (5.4) | O'Hare et al. 2009 | |||
| RET (7) | Mologni et al. 2013 | |||
| KIT (12.5) | O'Hare et al. 2009 | |||
|
| ||||
| Sunitinib | Sutent; SU-11248 | N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide | PDGFRβ (8)* | Mendel et al. 2003 |
| VEGFR2 (9)* | Mendel et al. 2003 | |||
| KIT (1-10)** | Abrams et al. 2003 | |||
| RET (30) | Mologni et al. 2013 | |||
| FLT3 (250) ** | O’Farrell et al. 2003 | |||
| FGFR1 (830)* | Mendel et al. 2003 | |||
|
| ||||
| Regorafenib | Stivarga; BAY 73-4506 | 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide | RET (1.5) | Wilhelm et al. 2011 |
| RAF1 (2.5) | ||||
| mVEGFR2 (4.2) | ||||
| KIT (7) | ||||
| VEGFR1 (13) | ||||
| PDGFRβ (22) | ||||
| BRAF (28) | ||||
| mVEGFR3 (46) | ||||
| FGFR1 (202) | ||||
| TIE2 (311) | ||||
|
| ||||
| Sorafenib | Nexavar; BAY 43-9006 | 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide | RET (5.9) | Plaza-Menacho et al. 2007 |
| RAF1 (6) | Wilhelm et al. 2004 | |||
| mVEGFR2 (15) | Wilhelm et al. 2004 | |||
| mVEGFR3 (20) | Wilhelm et al. 2004 | |||
| BRAF (22) | Wilhelm et al. 2004 | |||
| mPDGFRb (57) | Wilhelm et al. 2004 | |||
| FLT3 (58) | Wilhelm et al. 2004 | |||
| KIT (68) | Wilhelm et al. 2004 | |||
| VEGFR2 (90) | Wilhelm et al. 2004 | |||
2
Targets are ranked in descending order based on the efficacy of their inhibition: RET is highlighted. Data from in vitro kinase assays, in some cases from separate experiments (see References), are reported (standard deviations are omitted). Only targets with IC50 smaller than 1,000 nM are reported; based on the different experimental conditions (e.g. type of kinase assay, incubation time, concentration of ATP) direct comparisons between different compounds should be done cautiously.
*
Biochemical Ki values rather than IC50 are reported.
**
IC50 in cell-based phosphorylation assays