Focus on Azole-Based and Other N-Containing Heterocycles Within the Landscape of Current Structural Classes as Feline McDonough Sarcoma-Like Tyrosine Kinase 3 (FLT3) Inhibitors for Acute Myeloid Leukemia.

Abstract

Acute myeloid leukemia (AML) is the most common form of acute leukemia. It is characterized by unfavorable prognosis, elevated rates of recurrence, short overall survival and high mortality rates. Genetic and epigenetic aberrations contribute to its initiation and progression, presenting a considerable clinical challenge. Genomic investigations revealed that FMS-like tyrosine kinase 3 (FLT3), a receptor tyrosine kinase regulating the proliferation and differentiation of hematopoietic cells, is overexpressed in AML leukemic blasts. To date, FDA has approved only three FLT3 inhibitors for targeted AML therapy (midostaurin, gilteritinib, quizartinib). These molecules feature several nitrogen atoms; in particular quizartinib contains an oxazole and a urea group that are involved in interactions with FLT3 kinase domain. Similarly, different N-containing heterocycles have proven to play a key role in other FLT3 inhibitors. Though small-molecule FLT3 inhibitors encompass various chemical classes, N-containing heterocycles and particularly the azole core represent the most common scaffold. The electron-rich properties of the azoles allow them to easily bind with enzymes and receptors. Based on this, we will provide a general overview of FLT3 inhibitor classes in AML, along with a comprehensive report on azole-based structures, reviewing recent contributions to the field.