Drug Discovery - FLT3

About FLT3

Fms-Like Tyrosine Kinase 3 (FLT3) belongs to the type III receptor tyrosine kinase family and is highly expressed in most acute leukemias. Its ligand, FLT3-L, stimulates the proliferation of hematopoietic stem progenitor and dendritic cells. FLT-3 is expressed at very high levels in acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL). FLT-3/ITD (internal tandem duplication) mutation occurs in 15% to 35% of AML patients and promotes constitutive activation of the FLT-3 receptor. AML patients carrying the ITD mutations are found to have a decreased overall survival compared with patients without ITD mutations. Inhibition of FLT3 is therefore expected to be an effective strategy for the treatment of AML and potentially other leukemias.

Furthermore, high expression levels of FLT3 on early myeloid and lymphoid progenitors and dendritic cells suggest FLT3 inhibitors may have therapeutic utility in the treatment of Rheumatoid Arthritis, Multiple Sclerosis and other auto-immune disorders.

Small Molecule Inhibitors

Sareum has used its SKIL platform to develope a novel chemical series that inhibits the activity of FLT3 kinase and is highly selective against a panel of 29 other kinases. The X-ray crystal structures of the lead compounds in complex with a surrogate kinase have been solved to high resolution.

The compounds posses good physicochemical properties and good stability to liver microsomes. The compounds are readily synthesisable and offer excellent scope for further optimisation.

Related compounds within the series show good oral bioavailability (F=90%) and in-vivo T1/2 (>2Hr)

More information about this programme is available here: FLT3 (download pdf)