FLT3 inhibitors in clinical development (modified from Wadleigh et al29 ).
| Tyrosine Kinase Inhibitor . | Class . | Receptor Inhibitor Activity† . | FLT3 IC50‡ . | Clinical Trials/ Comments . | Toxicity . |
|---|---|---|---|---|---|
| † Receptor inhibitor activity in descending order of potency | |||||
| ‡ FLT3 autophosphorylation in vitro 1 | |||||
| Abbreviations: AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; MPD, myeloproliferative disease; MM, multiple myeloma | |||||
| PKC-412 | Benzoylstaurosporine | PKC PDGFR KDR KIT FLT3 ABL | 528 nM | Phase II: AML with/without FLT3-ITD In FLT 3 mut pts (n = 20), 35% significant reduction in blast count25 | Nausea, emesis, fatigue |
| CEP-701 | Indolocarbazole | FLT3 TRKA KDR PKC PDGFR EGFR | 2–3 nM | Phase II: AML with FLT3-ITD Several pts had reduced blast counts, autophosphorylation inhibited26 | Nausea, emesis, fatigue |
| MLN-518 | Piperazinyl quinazoline | KIT PDGFR FLT3 FMS | 170–220 nM | Phase I: AML/MDS with/without FLT3-ITD Phase II: AML with FLT3-ITD A few pts with FLT3 ITD treated at higher doses had biological response27 | Generalized weakness, fatigue, nausea and vomiting |
| SU5416 | Indolinone | FLT3 KDR KIT | 250 nM | Phase II: Refractory AML/MDS/MPD/MM Phase II: Refractory AML (c-KIT positive). No responses in FLT3 ITD pts.24 | Fatigue, nausea, sepsis and bone pain |
| Tyrosine Kinase Inhibitor . | Class . | Receptor Inhibitor Activity† . | FLT3 IC50‡ . | Clinical Trials/ Comments . | Toxicity . |
|---|---|---|---|---|---|
| † Receptor inhibitor activity in descending order of potency | |||||
| ‡ FLT3 autophosphorylation in vitro 1 | |||||
| Abbreviations: AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; MPD, myeloproliferative disease; MM, multiple myeloma | |||||
| PKC-412 | Benzoylstaurosporine | PKC PDGFR KDR KIT FLT3 ABL | 528 nM | Phase II: AML with/without FLT3-ITD In FLT 3 mut pts (n = 20), 35% significant reduction in blast count25 | Nausea, emesis, fatigue |
| CEP-701 | Indolocarbazole | FLT3 TRKA KDR PKC PDGFR EGFR | 2–3 nM | Phase II: AML with FLT3-ITD Several pts had reduced blast counts, autophosphorylation inhibited26 | Nausea, emesis, fatigue |
| MLN-518 | Piperazinyl quinazoline | KIT PDGFR FLT3 FMS | 170–220 nM | Phase I: AML/MDS with/without FLT3-ITD Phase II: AML with FLT3-ITD A few pts with FLT3 ITD treated at higher doses had biological response27 | Generalized weakness, fatigue, nausea and vomiting |
| SU5416 | Indolinone | FLT3 KDR KIT | 250 nM | Phase II: Refractory AML/MDS/MPD/MM Phase II: Refractory AML (c-KIT positive). No responses in FLT3 ITD pts.24 | Fatigue, nausea, sepsis and bone pain |