In this review, we discuss the studies that led to the inception of midostaurin as a targeted kinase inhibitor, its evaluation in AML, the early clinical trials and the large Phase III clinical trial that led to its eventual US FDA-approval in <i>FLT3-</i>mutated AML.
Internal tandem duplications (ITD) within the juxtamembrane domain of FMS-like tyrosine kinase 3 (FLT3) represent a poor prognostic indicator in acute myeloid leukemia (AML).
In this article, we review the current landscape of approved and investigational FLT3 inhibitors in AML, including the current standard of care and investigational strategies.
Here, we show that the triple combination of the differentiating agent retinoic acid (RA), the ER stress-inducing drug tunicamycin (Tm), and arsenic trioxide (ATO), able to generate oxidative stress, leads to the death of AML cell lines expressing fusion proteins involving the gene MLL and the internal tandem duplication (ITD) in the FLT3 tyrosine kinase receptor.
Internal tandem duplication (ITD) in the fms-like tyrosine kinase 3 (FLT3) gene is one of the most frequent genetic alteration in acute myeloid leukemia (AML), and it is associated with worse clinical outcome.
Genotypic mutation of fms like tyrosine kinase 3 (FLT3), Nucleophosmin (NPM1), and DNA-methyltransferase 3A (DNMT3A) has been involved in the leukemogenesis of acute myeloid leukemia (AML), with the well known poor prognostic role of FLT3 and DNMT3A and favorable role for the NPM1 mutation.
27 potently inhibits the proliferation of the FLT3-ITD-positive acute myeloid leukemia cancer lines through suppression of the phosphorylation of FLT3 kinase and downstream signaling pathways, induction of apoptosis, and arresting the cell cycle into the G0/G1 phase.
All of the derivatives displayed cytotoxicity against the human FLT-3 internal tandem duplication (ITD) mutant acute myeloid leukemia (AML) cell line MV4-11 with IC<sub>50</sub> values of 0.32-0.96 μM.
FMS-like tyrosine kinase 3 (<i>FLT3</i>) mutations are one of the most frequently encountered genetic alterations in acute myeloid leukemia (AML), and are generally associated with unfavorable outcomes.
In this update on the 27 patients with FLT3-mutated AML in our original report, we show persistence of the previously reported impressive long-term disease control.
Three mutation-specific targeted therapies have recently been approved by the FDA for the treatment of acute myeloid leukemia (AML): midostaurin for FLT3 mutations, enasidenib for relapsed or refractory cases with IDH2 mutations, and ivosidenib for cases with an IDH1 mutation.
Patients with atypical CK-AML differed from those with typical CK-AML: they carried TP53 mutations less often (P < 0.001) and more often PHF6 (P = 0.008), FLT3-TKD (P = 0.02), MED12 (P = 0.02), and NPM1 (P = 0.02) mutations.
Herein, we report a virtual screening strategy that led to the discovery of irreversible inhibitors of FMS-like tyrosine kinase 3 (FLT3) involved in the pathogenesis of acute myeloid leukemia.
When comparing patients with a low FLT3-ITD AR with those with a high FLT3-ITD AR, no significant differences in survival were noted among patients with nucleophosmin 1 (NPM1)-mutated AML (P = .28) or wild-type NPM1 (P = .35), and in those treated with IA alone (P = .79) or those treated with IA and a FLT3 inhibitor (P = .10).
In conclusion, the results of this study could provide valuable insights into discovery of new FLT3 inhibitors, and compound 46 was worthy of further development as potential drug candidate to treat AML.