Small molecules ATP-competitive inhibitors of FLT3: a chemical overview.

A review. FLT3 is a tyrosine kinase (TK), member of the class III TK receptor family, normally expressed in hematopoietic, immune and neural systems, also playing an important role in the pathogenesis of acute leukemias, particularly acute myeloid leukemia (AML), where it is present in constitutively activated mutated forms, correlated with poor prognosis, in a notable percentage of patients. For these reasons FLT3 soon appeared as a promising target for the therapeutic intervention for this severe and aggressive malignancy; the recent detn. of the crystal structure of the autoinhibited form of FLT3 gave new trend for the design and the synthesis of potent inhibitors. Small mols. tyrosine kinase inhibitors represent one of the largest drug family currently targeted by pharmaceutical companies for the treatment of cancer. Exciting examples of such mols. have reached advanced clin. trials and have been recently approved by FDA for the treatment of different solid or hematol. tumors. Usually TK inhibitors share common features, namely two hydrophobic/arom. regions bearing one or more hydrogen bonding substituents. These two regions can be connected by different spacers and almost all the mols. contain a component resembling the ATP purine structure. This review will deal with FLT3 synthetic inhibitors, reporting not only the most important mols. that are in clin. trials, but also the new compds. that have appeared in literature in the last few years. Our attention will be focused on chem. structures, mechanisms of action and structure-activity relationships.