A recent discovery of secondary mutations in the kinase domain of Fms-like tyrosine kinase 3 (FLT3) targeted by kinase inhibitor AC220 (quizartinib) established it as a relevant target in acute myeloid leukemia (AML). However, at the same time these observations suggest to identify next-generation inhibitors to target the resistant variants of FLT3. Here we show that SAR302503, a JAK2/FLT3 inhibitor in phase III trial for the treatment of polycythemia vera (PV) and myelofibrosis (MF), can potently inhibit FLT3-ITD variants that confer resistance to AC220. Interestingly, In vitro drug selection against SAR302503 at Cmax value (3 uM) failed to develop resistant clones suggesting it will be more effective in preventing the emergence of resistant clones. Structural modeling suggests that SAR302503 is a type I inhibitor that binds to ATP site in a DFG-in conformation. Altogether our data supports for clinical evaluation of SAR302503 for naïve and resistant variants of FLT3-ITD in AML patients to manage clinical resistance.

Disclosures:

No relevant conflicts of interest to declare.

Author notes

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Asterisk with author names denotes non-ASH members.

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