Tuesday, May 5, 2015

Drugs in Clinical Pipeline: Gilteritinib

Gilteritinib [6-ethyl-3-((3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide] an orally available FLT3/AXL inhibitor, showed potent antileukemic activity against Acute Myeloid Leukaemia (AML) with either or both FLT3-ITD and FLT3-D835 mutations. These findings support the development of Gilteritinib for the potential use in treating AML.

Of the 78 tyrosine kinases tested, Gilteritinib inhibited FLT3, LTK, ALK, and AXL kinases by over 50% at 1 nM with an IC50 value of 0.29 nM for FLT3, approximately 800-fold more potent than for c-KIT (IC50 = 230 nM), the inhibition of which is linked to a potential risk of myelosuppression. Inhibition values for other kinases are, TRKA (IC50 = 1.1 nM), RET (IC50 = 1.8 nM), ROS (IC50 = 1.5 nM) and MER (IC50 = 2.9 nM).

The activity of Gilteritinib is as follows:

IC50 (FLT3 enzyme assay) = 0.29 nM
IC50 (LTK enzyme assay) = 0.25 nM
IC50 (ALK enzyme assay) = 0.42 nM
IC50 (AXL enzyme assay) = 0.70 nM 

Common Name: Gilteritinib
Synonyms:  ASP2215; ASP-2215; ASP 2215
IUPAC Name: 6-ethyl-3-((3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide
CAS Number: 1254053-43-4; 1254053-84-3 (hemifumarate)
Mechanism of Action: Kinase Inhibitor; Fms-like Tyrosine Kinase 3 Inhibitors; Proto Oncogene Protein c-KIT Inhibitors
Indication: Treatment of Acute Myeloid Leukaemia; AML Therapy
Development Stage: Phase I/II
Company: Astellas Pharma

Gilteritinib inhibited the growth of MV4-11 cells, which harbor FLT3-ITD, with an IC50 value of 0.92 nM, accompanied with inhibition of pFLT3, pAKT, pSTAT5, pERK, and pS6. Gilteritinib also inhibited the growth of Ba/F3 cells expressing FLT3-ITD and/or FLT3-D835 mutation with similar activity. Colony formation of human granulocyte-macrophage decreased to 58% in response to Gilteritinib at 100 nM, more than 100-fold higher than required for MV4-11. In MV4-11 xenografted-mice, the concentration of Gilteritinib in tumors was more than 20-fold higher than that in plasma with oral administration of Gilteritinib at 10 mg/kg for 4 days. Treatment of Gilteritinib for 28 days resulted in dose-dependent inhibition of MV4-11 tumor growth and induced complete tumor regression at more than 6 mg/kg. Further, Gilteritinib decreased tumor burden in bone marrow and prolonged the survival of mice intravenously transplanted with MV4-11 cells [1].

1. Ueno, Y.; et. al. ASP2215, a novel FLT3/AXL inhibitor: Preclinical evaluation in acute myeloid leukemia (AML). J Clin Oncol 2014 32(suppl; abstr 7070).