Mutation within the FMS-like tyrosine kinase 3 (FLT3), the class III receptor tyrosine kinase (RTK) family, a gene on chromosome 13q12 has been detected in up to 35% of acute myeloid leukemia (AML) patients and represent one of the most frequently identified genetic alterations in AML. Two major classes of activating FLT3 mutations have been identified in AML patients: internal tandem duplications (ITD) and tyrosine kinase domain (TKD) point mutations. ITD-mutations cause constitutive activation of FLT3, leading to aberrant activation of multiple downstream pathways such as PI3K/AKT, MAPK/ERK, and STAT5. Also, about 5-10% of AML patients harbor point mutations within the second TKD. In most cases, these mutations result in a substitution of tyrosine for aspartic acid at codon 835 (D835Y). Similar to FLT3-ITDs, TKD-mutations cause constitutive activation of the FLT3 receptor, and aberrant activation of downstream signaling pathways. In this respect, FLT3 has emerged as a promising molecular target for therapy of AML.
SKI-G-801 (G-749 HCl salt), our candidate lead, showed highly potent and selective activity (single nM range) against ITD, D835Y, and other clinical known mutants in biochemical analysis and BaF3 model cells in comparison to competitors’ drug. Furthermore, it showed long-lasting inhibitory activity indicated by compound washing experiments although it is a reversible and ATP-competitive inhibitor. Such long-lasting efficacy may lead to strong induction of apoptosis of AML cancer cells.
SKI-G-801 is superior to known FLT3 inhibitors in terms of 1) prolonged activity against FLT3, 2) stronger inhibition of gatekeeper and TKD mutant, 3) stronger anti-leukemic activity in primary patient cells, and 4) stronger inhibition in bone marrow environment.
SKI-G-801 is in clinical phase 1 in the United States.