RESUMEN
Mutations of the type III receptor tyrosine kinase FLT3 occur in approximately 30% of acute myeloid leukemia patients and lead to constitutive activation. This has made FLT3-activating mutations an attractive drug target because they are probable driver mutations of this disease. As more potent FLT3 inhibitors are developed, a predictable development of resistance-conferring point mutations, commonly at residue D835, has been observed. Crenolanib is a highly selective and potent FLT3 tyrosine kinase inhibitor (TKI) with activity against the internal tandem duplication (FLT3/ITD) mutants and the FLT3/D835 point mutants. We tested crenolanib against a panel of D835 mutant cell lines and primary patient blasts and observed superior cytotoxic effects when compared with other available FLT3 TKIs such as quizartinib and sorafenib. Another potential advantage of crenolanib is its reduced inhibition of c-Kit compared with quizartinib. In progenitor cell assays, crenolanib was less disruptive of erythroid colony growth, which may result in relatively less myelosuppression than quizartinib. Finally, correlative data from an ongoing clinical trial demonstrate that acute myeloid leukemia patients can achieve sufficient levels of crenolanib to inhibit both FLT3/ITD and resistance-conferring FLT3/D835 mutants in vivo. Crenolanib is thus an important next-generation FLT3 TKI.
Asunto(s)
Antineoplásicos/farmacología , Bencimidazoles/farmacología , Resistencia a Antineoplásicos , Leucemia Mieloide Aguda/genética , Piperidinas/farmacología , Mutación Puntual , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Antineoplásicos/farmacocinética , Bencimidazoles/farmacocinética , Médula Ósea/metabolismo , Células de la Médula Ósea/citología , Ensayo de Unidades Formadoras de Colonias , Células HL-60 , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Piperidinas/farmacocinética , Pronóstico , Proteínas Proto-Oncogénicas c-kit/metabolismo , Análisis de Secuencia de ADN , Sales de Tetrazolio , Tiazoles , Factores de Tiempo , Tirosina Quinasa 3 Similar a fms/metabolismoAsunto(s)
Antineoplásicos/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Aminopiridinas/uso terapéutico , Benzotiazoles/uso terapéutico , Biomarcadores/análisis , Médula Ósea/efectos de los fármacos , Médula Ósea/enzimología , Médula Ósea/patología , Línea Celular Tumoral , Ensayos Clínicos como Asunto , Dasatinib , Expresión Génica , Cabello/efectos de los fármacos , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/enzimología , Células Madre Hematopoyéticas/patología , Humanos , Indazoles , Leucemia Mieloide Aguda/enzimología , Leucemia Mieloide Aguda/patología , Niacinamida/análogos & derivados , Niacinamida/uso terapéutico , Compuestos de Fenilurea/uso terapéutico , Pigmentación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/metabolismo , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Sorafenib , Sulfonamidas/uso terapéutico , Tiazoles/uso terapéutico , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
There have been a number of clinical trials testing the efficacy of FMS-like tyrosine kinase-3 (FLT3) tyrosine kinase inhibitors (TKI) in patients with acute myeloid leukemia (AML) harboring a constitutively activating mutation in FLT3. However, there has been limited efficacy, most often because of inadequate achievement of FLT3 inhibition through a variety of mechanisms. In a previous study, TTT-3002 was identified as a novel FLT3 inhibitor with the most potent activity to date against FLT3 internal tandem duplication (FLT3/ITD) mutations. Here, the activity of TTT-3002 is demonstrated against a broad spectrum of FLT3-activating point mutations, including the most frequently occurring D835 mutations. The compound is also active against a number of point mutations selected for in FLT3/ITD alleles that confer resistance to other TKIs, including the F691L gatekeeper mutation. TTT-3002 maintains activity against patients with relapsed AML samples that are resistant to sorafenib and AC220. Studies utilizing human plasma samples from healthy donors and patients with AML indicate that TTT-3002 is only moderately protein bound compared with several other TKIs currently in clinical trials. Tumor burden of mice in a FLT3 TKI-resistant transplant model is significantly improved by oral dosing of TTT-3002. Therefore, TTT-3002 has demonstrated preclinical potential as a promising new FLT3 TKI that may overcome some of the limitations of other TKIs in the treatment of FLT3-mutant AML. Cancer Res; 74(18); 5206-17. ©2014 AACR.