Small-Molecule Fms-like Tyrosine Kinase 3 Inhibitors: An Attractive and Efficient Method for the Treatment of Acute Myeloid Leukemia

Abstract

Fms-like tyrosine kinase 3 (FLT3) is an important member of the class III receptor tyrosine kinase (RTK) family, which is involved in the proliferation of hematopoietic cells and lymphocytes. In recent years, increasing evidence have demonstrated that the activation and mutation of FLT3 is closely implicated in the occurrence and development of acute myeloid leukemia (AML). The exploration of small-molecule inhibitors targeting FLT3 has aroused wide interest of pharmaceutical chemists and is expected to bring new hope for AML therapy. In this review, we specifically highlighted FLT3 mediated JAK/STAT, RAS/MAPK, and PI3K/AKT/mTOR signaling. The structural properties and biological activities of representative FLT3 inhibitors reported from 2014 to the present were also summarized. In addition, the major challenges in the current advance of novel FLT3 inhibitors were further analyzed, with the aim to guide future drug discovery.

3H-Pyrazolo[4,3-f]quinoline-Based Kinase Inhibitors Inhibit the Proliferation of Acute Myeloid Leukemia Cells In Vivo

“…In the last few years, many groups have demonstrated that the concurrent inhibition of FLT3 and other kinases that promote the survival of leukemia cells results in enhanced leukemia cell killing. 6,7 Several potential therapeutic examples, including cooperation with cyclin-dependent kinases (CDKs), JAK2, MEK, Mer, or Pim, have been described (Figure 1). 8−11 In our previous work, we found that compounds based on the 8,9,10,11-tetrahydro-3H-pyrazolo [4,3-a]phenanthridine scaffold are potent FLT3 inhibitors and effectively kill FLT3-driven AML cell lines and we introduced the candidate molecule 10 (HSD1169) (Figure 1), 12 whereas six-and seven-membered rings in this novel scaffold afforded potent FLT3 inhibitors, a five-membered ring analogue of 10 was less active, and a fourmembered ring or the acyclic methyl group analogues were poor inhibitors of FLT3.…”

“…Therefore, despite the successful drug approvals, the necessity of the continual development of novel entities that inhibit FLT3 as well as other oncogenic kinases and/or targets is still relevant. In the last few years, many groups have demonstrated that the concurrent inhibition of FLT3 and other kinases that promote the survival of leukemia cells results in enhanced leukemia cell killing. , Several potential therapeutic examples, including cooperation with cyclin-dependent kinases (CDKs), JAK2, MEK, Mer, or Pim, have been described (Figure ). − …”

Discovery of a Potent FLT3 Inhibitor (LT-850-166) with the Capacity of Overcoming a Variety of FLT3 Mutations

“…Acute myeloid leukemia (AML) belongs to hematopoietic malignancies with strong invasiveness and high heterogeneity characteristics, which mainly manifests as deregulation of proliferation, obstruction of differentiation, and apoptosis of hematopoietic progenitor cells . It is estimated that the 5-year overall survival (OS) of AML patients is less than 50%. , In addition, according to the estimation of the American Cancer Society in 2021, the number of new-onset AML cases and deaths would increase to 20,240 and 11,400, respectively; meanwhile, AML accounted for a large proportion of annual deaths due to leukemias in the United States . Recently, the World Health Organization (WHO), the National Comprehensive Cancer Network (NCCN), and the European leukemiaNet (ELN) all have established the guidelines for AML classification and risk stratification. ,, Therefore, it is urgent to develop effective strategies for the treatment of AML patients.…”

“…Targeted therapy against tumors has exhibited great promise and developed into one of the major therapeutic strategies for tumor treatment . To date, Fms-like tyrosine kinase 3 (FLT3) is among the most striking targets for AML therapy, which is coded by FLT3 gene, and belongs to the class III receptor tyrosine kinase (RTK) family, sharing high-sequence similarities with c-KIT, c-FMS, and platelet-derived growth factor receptor (PDGFR) . FLT3 regulates proliferation and differentiation of hematopoietic progenitor cells in bone marrow and plays a significant role in hematopoiesis and leukemogenesis. − Mutations in the FLT3 gene are found in approximately 30% of AML patients, including the internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations, accounting for approximately 23 and 7%, respectively .…”

“…FLT3 regulates proliferation and differentiation of hematopoietic progenitor cells in bone marrow and plays a significant role in hematopoiesis and leukemogenesis. − Mutations in the FLT3 gene are found in approximately 30% of AML patients, including the internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations, accounting for approximately 23 and 7%, respectively . FLT3 mutations can lead to ligand-independent dimerization and autophosphorylation and constitutively activate FLT3 downstream signaling pathways [such as Ras/mitogen-activated protein kinase (MAPK), phosphatidylinositol-3-kinase (PI3K)/AKT, and signal transducer activator of transcription 5 (STAT5)], promoting survival and proliferation of AML cells eventually. − In general, AML patients with FLT3-ITD mutations have poor prognosis and high relapse and mortality rate; yet, the relationship between FLT3-TKD mutations and prognosis of AML patients is indistinct. − Furthermore, the simultaneous occurrence of FLT3-ITD and FLT3-TKD mutations confers drug resistance to clinical FLT3 inhibitors. , Targeting FLT3 mutations for AML is attracting sustaining research interests. , …”