Lestaurtinib, a multitargeted tyrosine kinase inhibitor: from bench to bedside.
BACKGROUND
Internal tandem duplication of the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD) is a common recurring mutation in acute myeloid leukemia (AML) with normal karyotype, and the presence of FLT3-ITD confers a poor prognosis on this large subgroup of AML patients. Since the discovery of lestaurtinib as a potent FLT3 inhibitor, in 1985, there has been considerable interest in the development of this agent (CEP-701, Cephalon, Frazer, PA, USA) for treatment of this population.


METHODS
An extensive literature search was conducted that included published articles and abstracts on the preclinical and clinical development of this agent spanning the last decade.


RESULTS
The review describes the historical development of this agent and reviews the available preclinical and clinical data on lestaurtinib and expands on potential future directions in development of this agent.


CONCLUSIONS
Lestaurtinib is a multi targeted tyrosine kinase inhibitor which has been shown to potently inhibit FLT3 at nanomolar concentrations in preclinical studies, leading to its rapid development as a potential targeted agent for treatment of AML. Phase I studies have shown lestaturtinib to be an active agent particularly when used in combination with cytotoxic drugs. Currently, Phase II and Phase III studies are underway aiming to establish the future of this agent as a treatment option for patients with FLT3-ITD AML.
Medical University of South Carolina, Hematology and Oncology, 96 Jonathan Lucas Street, CSB 903, Charleston, SC 29425, USA.
Munira
M
Shabbir
Robert
R
Stuart
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002227:Carbazoles / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D005663:Furans; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D002227:Carbazoles; D005663:Furans; D047428:Protein Kinase Inhibitors; C119379:lestaurtinib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3