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FLT3: A Receptor Tyrosine Kinase Target in Adult and Pediatric AML
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Mark Levis, Patrick Brown, Donald Small
The indolocarbazoles lestaurtinib (CEP-701) and midostaurin (PKC412) have both been studied in vitro using combinations with chemotherapy. In one study, lestaurtinib (CEP-701) combined with cytarabine, daunorubicin, etopo-side, and mitoxantrone was tested on FLT3 mutant cell lines as well as in a primary AML sample harboring an FLT3/ITD mutation (165). Three treatment sequences were examined: (1) pretreatment of leukemia cells with lestuartinib followed by one of the chemotherapeutic agents, (2) simultaneous treatment with lestaurtinib and chemotherapy, and, finally, (3) exposure of cells to chemotherapy followed by lestaurtinib. Pretreatment with lestaurtinib antagonized the cytotoxic effects of the chemotherapy. This was presumably because FLT3 inhibition induced a cell cycle arrest, which, in turn, blunted the S-phase selective effects of agents such as cytarabine and etoposide. Simultaneous treatment with chemotherapy, or lestaurtinib exposure after chemotherapy, induced synergistic cytotoxicity. However, a potential pharmacodynamic interaction between lestaurtinib and daunorubicin was identified because both drugs are bound in plasma to α-1 acid glycoprotein (AAG), free levels of the anthra-cycline could result if they were to be administered simultaneously. Therefore, the conclusion drawn from this work was that chemotherapy treatment followed by the FLT3 inhibitor offered the most potential for safety and efficacy. In another study, lestaurtinib and midostaurin were compared for cytotoxic effect against primary AML cells, alone and in combination with cytarabine (166). Lestaurtinib was found to be synergistic with cytarabine in inducing cytotoxicity in primary samples with mutant, but not wild-type, FLT3.
Drug discovery for primary amebic meningoencephalitis: from screen to identification of leads
Published in Expert Review of Anti-infective Therapy, 2021
A subset of compounds available in a high-value Repurposing, Focused Rescue and Accelerated MEdicinal chemistry (ReFRAME) library also identified FDA-approved panobinostat displaying a nanomolar potency. In addition, FDA orphan drug lestaurtinib was also found highly potent against N. fowleri [38]. Another FDA-approved drug auranofin was identified as a priority anti-N. fowleri compound in this study (Table 1). Auranofin, a broad-spectrum anti-parasitic agent, was shown to be active against the US strains [39], as well as against the strains of various genotypes originated from different geographic regions [40]. Auranofin is a known inhibitor of selenoprotein synthesis [41] and thioredoxin reductase function [42–46], which is involved in protecting cells from damage caused by oxidative stress. Consistent with the targeting of redox enzymes, exposure to auranofin led to accumulation of reactive oxygen species in N. fowleri trophozoites [40].
Therapy of acute myeloid leukemia: therapeutic targeting of tyrosine kinases
Published in Expert Opinion on Investigational Drugs, 2019
In two phase III trials (UK AML15 and AML17), lestaurtinib plus standard chemotherapy did not show significant differences in outcomes versus chemotherapy alone [73,74]. However, it is noted that correlative studies had shown OS benefit in patients achieving greater than 85% in vivo FLT3 inhibition but unfortunately, plasma levels did not predict for in vivo inhibition [75]. Further clinical development of lestaurtinib has been discontinued given its relative lack of efficacy.