Tp-0903, A Novel Axl Inhibitor With Activity In Drug Resistant Flt3-Itd+ Aml Through A Mechanism That Includes Flt3 Inhibition

Abnormal expression of receptor tyrosine kinase Axl has been associated with poor prognosis in different cancers including acute myeloid leukemia (AML) and has been linked to drug resistance against chemotherapy as well as targeted therapies including FLT3 inhibitors (Park et al. Leukemia 2015). With its role in tumorigenesis, Axl has been actively pursued as a potential therapeutic target with small molecule inhibitors. TP-0903, a type I inhibitor, was designed in silico on an Axl scaffold that does not clash with the Axl gatekeeper residue, Leu620 (Mollard et al. ACS Med Chem Lett 2011). Since Axl inhibitors are known to also interact with FLT3 (Myers et al. J Med Chem 2016), we evaluated the hypothesis that TP-0903 demonstrates preclinical activity against FLT3 -ITD+AML through a mechanism that potentially involves both Axl and FLT3 inhibition.