Investigational drugs targeting FLT3 for leukemia

Abstract

FMS-like tyrosine kinase-3 (FLT3) is a member of the class III membrane receptor tyrosine kinase family and is important in survival, proliferation and differentiation of hematopoietic cells. FLT3 is mutated in ∼ 30% of acute myelogenous leukemia patients. These mutations involve internal tandem duplications in the juxtamembrane domain of the receptor and tyrosine kinase point mutations in the activation loop. Over the past decade, due to the incidence and poor prognosis associated with FLT3, numerous agents have been developed to directly inhibit the activity of wild type and mutated FLT3. In this review, we focus on the preclinical data demonstrating in vitro activity, inhibition of downstream signaling pathways and potential synergy with traditional chemotherapeutic agents. Also, early clinical trial data specifically focusing on drug toxicity, clinical efficacy and future directions of FLT3-directed anticancer therapy are discussed.

Keywords::

• acute myelogenous leukemia
• drug development
• FLT3
• internal tandem duplications
• tyrosine kinase domain