title: Small molecules ATP-competitive inhibitors of FLT3: a chemical overview.
abstract: 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 determination of the crystal structure of the autoinhibited form of FLT3 gave new trend for the design and the synthesis of potent inhibitors. Small molecules tyrosine kinase inhibitors represent one of the largest drug family currently targeted by pharmaceutical companies for the treatment of cancer. Exciting examples of such molecules have reached advanced clinical trials and have been recently approved by FDA for the treatment of different solid or haematological tumors. Usually TK inhibitors share common features, namely two hydrophobic/aromatic regions bearing one or more hydrogen bonding substituents. These two regions can be connected by different spacers and almost all the molecules contain a component resembling the ATP purine structure. This review will deal with FLT3 synthetic inhibitors, reporting not only the most important molecules that are in clinical trials, but also the new compounds that have appeared in literature in the last few years. Our attention will be focused on chemical structures, mechanisms of action and structure-activity relationships.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Genova, Viale Benedetto XV, 3, I-16132, Genova, Italy. schensil@unige.it
authors.forename: S
authors.initials: S
authors.lastname: Schenone
authors.forename: C
authors.initials: C
authors.lastname: Brullo
authors.forename: M
authors.initials: M
authors.lastname: Botta
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000473:pathology; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000255:Adenosine Triphosphate; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3