Quizartinib for the treatment of FLT3/ITD acute myeloid leukemia
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FLT3/ITD acute myeloid leukemia is a poor prognosis disease driven by a constitutively activated receptor tyrosine kinase, making it an obvious target for drug development. The development of clinically effective FLT3 inhibitors has been slow, in part because many are multi-targeted inhibitors that are not selective or specific for FLT3. Quizartinib is the first small molecule FLT3 tyrosine kinase inhibitor expressly developed as a FLT3 inhibitor. It is potent, selective and has ideal pharmacokinetics in comparison to other compounds previously tested. This article summarizes its advantages and limitations, and details the insights into the biology of the disease that have been uncovered through the laboratory and clinical use of quizartinib.Keywords:
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Background. FLT3 is a class III receptor tyrosine kinase expressed in normal stem cells and blasts of myeloid leukemia. Internal tandem duplication (ITD) of the FLT3 ge- ne affecting the exons 14 and 15 leads to ligand-independent FLT3 dimerization and constitutive activation. This stimula- tes proliferation and induces inhibition of apoptosis which contributes to leukemogenesis. We have screened a panel of acute myeloid leukemia (AML) patients for the occurrence of FLT3/ITD mutation and correlated this mutation to patients' survival and basic hematological parameters.
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FLT3/ITD acute myeloid leukemia is a poor prognosis disease driven by a constitutively activated receptor tyrosine kinase, making it an obvious target for drug development. The development of clinically effective FLT3 inhibitors has been slow, in part because many are multi-targeted inhibitors that are not selective or specific for FLT3. Quizartinib is the first small molecule FLT3 tyrosine kinase inhibitor expressly developed as a FLT3 inhibitor. It is potent, selective and has ideal pharmacokinetics in comparison to other compounds previously tested. This article summarizes its advantages and limitations, and details the insights into the biology of the disease that have been uncovered through the laboratory and clinical use of quizartinib.
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Gastrointestinal stromal tumors (GISTs) are prototypes of stem cell factor receptor (c-KIT)-driven cancer. Two receptor tyrosine kinases, c-KIT and fms-tyrosine kinase (FLT3), are frequently mutated in acute myeloid leukemia (AML) patients, and these mutations are associated with poor prognosis. In this study, we discovered a multitargeted tyrosine kinase inhibitor, compound 15a, with potent inhibition against single or double mutations of c-KIT developed in GISTs. Moreover, crystal structure analysis revealed the unique binding mode of 15a with c-KIT and may elucidate its high potency in inhibiting c-KIT kinase activity. Compound 15a inhibited cell proliferation and induced apoptosis by targeting c-KIT in c-KIT-mutant GIST cell lines. The antitumor effects of 15a were also demonstrated in GIST430 and GIST patient-derived xenograft models. Further studies demonstrated that 15a inhibited the proliferation of c-KIT- and FLT3-driven AML cells in vitro and in vivo. The results of this study suggest that 15a may be a potential anticancer drug for the treatment of GISTs and AML.
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KIT and FLT3 are class III trans membrane tyrosine kinases playing key roles in the control of hematopoietic stem cell survival and proliferation. KIT is mutated in about 2.5-3% of acute myeloid leukemia (AML) patients mainly by point mutations occurring at the level of tyrosine kinase domains. FLT3 is mutated in about 30% of AML patients, either by internal tandem duplication of the juxtamembrane domain or by point mutations occurring at the level of tyrosine kinase domains. All these types of mutations lead to the constitutive activation of KIT and FLT3 receptors, respectively. In some AML subsets, the occurrence of FLT3/ITD mutation is associated with a poor prognosis. These observations have represented the basis for the development of a large number of Tyrosine Kinase Inhibitors (TKIs) with activity against KIT and FLT3. Some of these inhibitors are still in the preclinical phase, but many have been tested in phase I/II/III clinical studies. Although these inhibitors when used as single agents have lead to a significant reduction of the number of leukemic blasts, they have produced only transient and limited clinical responses. This efficacy may be related to the limited inhibitory caefficacy of these inhibitors, occurrence of resistance and to the complexity of the genetic abnormalities occurring in AMLs. However, recently Quizartinib, a potent FLT3 inhibitor, showed an impressive rate of remission induction in patients with chemotherapy-refractory FLT3-ITD-positive AMLs, but most remissions do not meet classical criteria of complete remissions and instead represent clearance of bone marrow blasts with incomplete recovery of blood cell counts. However, the majority of these patients after an initial sustained response exhibit a leukemic relapse due to the rare pre-exisisting or new FLT3-ITD-TKD mutants surviving to the treatment with this drug and becaming driver leukemic clones. The combination of various types of FLT3 TKIs, including a type II TKI like Quizartinib with a type I FLT3 inhibitor efficiently targeting TKD mutants, such as Crenolanib, or the combination of FLT3 inhibitors with other molecularly targeted agents inhibiting other pathways activated in leukemic cells would determine a major progress in leukemia therapy. The efficacy of FLT3 TKIs in combination with standard anti-leukemic chemotherapeutics is also under evaluation in several combination clinical trials. It is expected that these trials could determine an improvement in the negative prognosis of AML patients with FLT3/ITD mutations. Keywords: Membrane tyrosine kinase receptors, leukemia, cytogenetic.
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Membrane Tyrosine Kinase Receptors are an Important Target for the Therapy of Acute Myeloid Leukemia
KIT and FLT3 are class III trans membrane tyrosine kinases playing key roles in the control of hematopoietic stem cell survival and proliferation. KIT is mutated in about 2.5-3% of acute myeloid leukemia (AML) patients mainly by point mutations occurring at the level of tyrosine kinase domains. FLT3 is mutated in about 30% of AML patients, either by internal tandem duplication of the juxtamembrane domain or by point mutations occurring at the level of tyrosine kinase domains. All these types of mutations lead to the constitutive activation of KIT and FLT3 receptors, respectively. The occurrence of FLT3/ITD mutation is associated with a poor prognosis. These observations have represented the basis for the development of a relatively large number of Tyrosine Kinase Inhibitors (TKI) with activity against KIT and FLT3. The majority of these inhibitors are still in the preclinical phase of study, while few of them have been tested in phase I/II clinical studies. Although these inhibitors when used as single agents have lead to a significant reduction of the number of leukemic blasts, they have produced only transient and limited clinical responses. This efficacy may be related to the occurrence of resistance and to the complexity of the genetic abnormalities occurring in AMLs. The efficacy of FLT3 TKIs in combination with standard anti-leukemic chemotherapeutics has been evaluated in preclinical models and several combination clinical trials are ongoing and have been planned. It is expected that these trials could determine an improvement in the negative prognosis of AML patients with FLT3/ITD mutations. Finally, the combination of FLT3 TKIs with other molecularly targeted agents inhibiting other pathways activated in leukemic cells would determine a major progress in leukemia therapy. Keywords: Tyrosine Kinases catalytic domain, Homeobox gene, c-Kit, KIT signaling, juxtamembrane domain, FMS-LIKE TYROSINE KINASE
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The receptor tyrosine kinase FLT3 is an important regulatory molecule in hematopoiesis and is expressed on the blasts in most cases of acute leukemia. Activating mutations of this receptor are present in roughly 30% of acute myeloid leukemia (AML) patients and are associated with a distinctly worse clinical outcome. Efforts to target this mutation and improve outcomes in this subgroup of AML patients have led to the investigation of several novel small-molecule FLT3 tyrosine kinase inhibitors. These compounds derive from a wide variety of chemical classes and differ significantly in both their potency and selectivity. this review summarizes the data validating FLT3 as a therapeutic target in AML and reviews the results of preliminary clinical trials using these agents for the treatment of AML patients harboring FLT3 mutations.
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FLT3, a tyrosine kinase receptor, is the most common mutation in AML and has two classes of mutations: internal tandem duplications in the juxtamembrane domain (FLT3-ITDs) and point mutations in the tyrosine kinase domain (FLT3-TKDs). AML patients with FLT3 mutations tend to have a poor prognosis. As an independent factor, the presences of FLT3 mutations play an important role in the origin and development of AML and have prognostic value. Molecular targeted therapy represents a novel and popular therapeutic approach in the world. In this review, we explain clinical value of the FLT3 mutations, mechanism and research progression of the FLT3 inhibitor;and discuss difficulties and perspectives in the research of the FLT3 inhibitor.
Key words:
Receptor protein-tyrosine kinases; Mutation; Inhibins; Leukemia,myelocytic,acute
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Acute myeloid leukemia (AML) is a heterogeneous disease. Numerous molecular abnormalities have been identified in AML and, amongst these, FMS‑like tyrosine kinase 3 (FLT3) mutations are one of the most common somatic alterations detected. In the present study, an in vitro investigation was performed to evaluate the effects of all‑trans retinoic acid (ATRA) and PKC412, alone and in combination, in FLT3‑mutated AML cell lines. Trypan blue exclusion test, as well as morphological, western blot and isobologram analyses were conducted. The results indicated that the combined ATRA and PKC412 treatment exhibited additive or synergistic effects in FLT3‑mutated AML cell lines. These results provided in vitro evidence for the future clinical trials evaluating the effects of a combination treatment using PKC412 and ATRA on AML patients with FLT3‑mutations.
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