**1. Introduction**

Acute myeloid leukemia (AML) is a heterogeneous malignant disease, characterized by uncontrolled proliferation with impaired differentiation of myeloid progenitor cells and aggressive clinical course. In the past two decades the treatment landscape of AML underwent significant changes due to explosive growth in knowledge of the molecular pathways involved in the AML origin and course evolution. This increased new data and understanding of the pathogenesis of AML, facilitated the development of new drugs in the treatment of AML, particularly the creation of drugs that target the disease on a molecular level. Encouraging efficacy of targeted therapy when combined with the traditional chemotherapy have resulted in big improvement to AML treatment and survival. In this chapter, we will discuss the drugs used in treatment of AML, including targeted treatment strategies that have recently entered the clinical practice.

#### **1.1 Signaling and kinase pathway mutations inhibitors**

#### *1.1.1 FLT3 tyrosine kinase inhibitors*

Full-length human FLT3 was cloned from a pre-B cell library in 1993 [1], from a CD34+ hematopoietic stem cell-enriched library [2], and is located on chromosome 13q12 [3]. FLT3 is a member of class III receptor tyrosine kinases (RTK) [4] and its activation leads to promotion of cell survival, proliferation, and differentiation

through various signaling pathways, including PI3K, RAS, and STAT5 [5]. It is present in approximately 20–30% of adult AML patients and 5–15% of pediatric AML patients [6, 7]. FLT3-ITD mutations are associated with higher relapse rate and poorer overall survival, particularly with a high ratio of mutant allelic burden [8, 9]. Several first- and next generation FLT3 inhibitors have been investigated in patients with FLT3-ITD-mutated AML.

## *1.1.1.1 First-generation FLT3 inhibitors*
