Discovery of selective, metabolically stable pyrazole-based FLT3 inhibitors for the treatment of acute myeloid leukemia.

Acute myeloid leukemia (AML) is the most prevalent form of acute leukemia in adults, representing a substantial medical need, as the standard of care has not changed for the past two decades, and the long-term outcome remains dismal for a large fraction of patients. Approximately 30% of AMLs carry activating mutations of the FLT3 kinase. Unfortunately, single-agent FLT3 inhibitor therapy has met limited clinical efficacy, underscoring a strong rationale for the development of more selective and more potent inhibitors.