TG101348
 | |
| Names | |
|---|---|
| IUPAC name
N-tert-Butyl-3-{5-methyl-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide | |
| Other names
SAR302503 | |
| Identifiers | |
936091-26-8  | |
| Jmol-3D images | Image |
| |
| Properties | |
| Molecular formula |
C27H36N6O3S |
| Molar mass | 524.68 g·mol−1 |
| Density | 1.247 ± 0.06 g/cm3 |
| Except where noted otherwise, data is given for materials in their standard state (at 25 °C (77 °F), 100 kPa) | |
| Infobox references | |
TG101348 (SAR302503) is an orally available inhibitor of Janus kinase 2 (JAK-2) developed for the treatment of patients with myeloproliferative diseases including myelofibrosis. TG101348 acts as a competitive inhibitor of protein kinase JAK-2 with IC50=6 nM; related kinases FLT3 and RET are also sensitive, with IC50=25 nM and IC50=17 nM, respectively. Significantly less activity was observed against other tyrosine kinases including JAK3 (IC50=169 nM).[1] In treated cells the inhibitor blocks downstream cellular signalling (JAK-STAT) leading to suppression of proliferation and induction of apoptosis.
Myelofibrosis is a myeloid malignancy associated with anemia, splenomegaly, and constitutional symptoms. Patients with myelofibrosis frequently harbor JAK-STAT activating mutations that are sensitive to TG101348. Phase I trial results focused on safety and efficacy of TG101348 in patients with high- or intermediate-risk primary or post–polycythemia vera/essential thrombocythemia myelofibrosis have been published in 2011.[2]
Compound was originally discovered TargeGen then acquired by Sanofi-Aventis who continues its development under the code SAR302503.
References
- ↑ Pardanani, A.; Hood, J.; Lasho, T.; Levine, R. L.; Martin, M. B.; Noronha, G.; Finke, C.; Mak, C. C.; Mesa, R.; Zhu, H.; Soll, R.; Gilliland, D. G.; Tefferi, A. (2007). "TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations". Leukemia 21 (8): 1658–1668. doi:10.1038/sj.leu.2404750. PMID 17541402.
- ↑ Pardanani, A.; Gotlib, J. R.; Jamieson, C.; Cortes, J. E.; Talpaz, M.; Stone, R. M.; Silverman, M. H.; Gilliland, D. G.; Shorr, J.; Tefferi, A. (2011). "Safety and Efficacy of TG101348, a Selective JAK2 Inhibitor, in Myelofibrosis". Journal of Clinical Oncology 29 (7): 789–796. doi:10.1200/JCO.2010.32.8021. PMID 21220608.