Table 1.
Specification of inhibitors used in this study
| Name | Known targets | Result of target inhibition (drug action) | Clinical application | Cmax in μM (at dose/day) | Concentration range (μM)1 | Supplier2 |
|---|---|---|---|---|---|---|
| R763 | JAK2, aurora kinase A, aurora kinase B, FLT3 | G2/M phase arrest, endoreduplication | Phase 1 trial (human): 11.4-85.3 mg/day | 0.09 (85.3 mg) | 0.005-5 | Rigel Pharmaceuticals |
| TG101348 | JAK2, JAK1, JAK3, FLT3, RET, TYK2 | proliferation inhibition, apoptosis induction | Phase 1 trial (human): 100–600 mg/day | 2.8 (500 mg) | 0.005-7.5 | ChemieTek |
| AZD1480 | JAK2, JAK1, JAK3, TYK2, FGFR3, STAT3 | Proliferation inhibition, apoptosis induction | Phase 1 trial (human): 5–80 mg/day | 1.7 (30 mg) | 0.005-7.5 | ChemieTek |
| Ruxolitinib | JAK2, JAK1, JAK3 | Proliferation inhibition, apoptosis induction | Approved (human): PMF, post-PV-MF, post-ET-MF, PV3, (EU, USA) | 2.3 (50 mg) | 1-20 | ChemieTek |
| Pimozide | STAT5, D2 dopamine receptor, 5-HT7 receptor, Ca2+ channels | Unknown | Approved (human): Tourette's Syndrome (EU, USA) | 0.007 (2 mg) | 0.5-25 | Sigma-Aldrich |
| Piceatannol | STAT5, SYK, LCK | Proliferation inhibition, apoptosis induction, histamine release blockade | Animal model (rat): 20.2-80.7 mg/kg/day | 8.1 (80.7 mg/kg) | 1-75 | Sigma-Aldrich |
| Imatinib | KIT, BCR-ABL, PDGFR | Proliferation inhibition | Approved (human): CML, ALL, MDS/MPD, DFSP, HES/CEL, ASM, GIST (EU, USA) | 3.3 (400 mg) | 0.05-2.5 | ChemieTek |
| Masitinib | KIT, PDGFR, LCK, LYN, FGFR3 | Proliferation inhibition | Approved (canine): MCT (EU, USA—conditionally) | 0.9 (8.4 mg/kg) | 0.05-5 | LC Laboratories |
| Midostaurin | KIT, PKC, PKA, S6, EGFR, PDGFR | Proliferation inhibition, G2/M phase arrest | Approval pending (human): AML, mastocytosis (USA) | 7 (250 mg) | 0.05-2.5 | LC Laboratories |
| Nilotinib | KIT, BCR-ABL, PDGFR | Proliferation-/migration inhibition, apoptosis induction | Approved (human): CML (EU, USA) | 3.6 (800 mg) | 0.05-5 | ChemieTek |
| Toceranib | KIT, VEGFR, PDGFR, CSF-1, FLT3 | Proliferation inhibition, apoptosis induction | Approved (canine): MCT (EU, USA) | 0.3 (1.45 mg/kg) | 0.25-0.5 | Sigma-Aldrich |
Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myelogenous leukemia; ASM, aggressive systemic mastocytosis; Cmax, peak plasma concentration of a drug after administration; CML, chronic myelogenous leukemia; CSF-1, colony stimulating factor 1; DFSP, dermatofibrosarcoma protuberans; EGFR, epidermal growth factor receptor; ET, essential thrombocythemia; FGFR3, fibroblast growth factor receptor 3; FLT3, fms-like tyrosine kinase 3; GIST, gastrointestinal stromal tumor; HES/CES, hypereosinophilic syndrome/chronic eosinophilic leukemia; JAK, janus kinase; LCK, leukocyte C-terminal SRC kinase; LYN, LCK/YES novel tyrosine kinase; MCT, mast cell tumor; MDS/MPD, myelodysplastic/myeloproliferative disease; PDGFR, platelet-derived growth factor receptor; PK, protein kinase; PMF, primary myelofibrosis; PV, polycythemia vera; STAT, signal transducer and activator of transcription; SYK, spleen tyrosine kinase; TYK2, tyrosine kinase 2; VEGFR, vascular endothelial growth factor receptor.
Range of concentrations used in this study.
ChemieTek, Indianapolis, Indiana; LC Laboratories, Woburn, Massachusetts; Rigel Pharmaceuticals, San Francisco, California; Sigma-Aldrich, St. Louis, Missouri.
PV patients intolerant or resistant to hydroxyurea.