A novel, dual pan-PIM/FLT3 inhibitor SEL24 exhibits broad therapeutic potential in acute myeloid leukemia
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Wojciech Czardybon1,*, Renata Windak1,*, Aniela Gołas1, Michał Gałęzowski1, Aleksandra Sabiniarz1, Izabela Dolata1, Magdalena Salwińska1, Paweł Guzik1, Magdalena Zawadzka1, Ewelina Gabor-Worwa1, Bożena Winnik1, Małgorzata Żurawska1, Ewa Kolasińska1, Ewelina Wincza1, Marta Bugaj1, Monika Danielewicz1, Eliza Majewska1, Milena Mazan1, Grzegorz Dubin2, Monika Noyszewska-Kania3, Ewa Jabłońska3, Maciej Szydłowski3, Tomasz Sewastianik3, Bartosz Puła5, Anna Szumera-Ciećkiewicz4, Monika Prochorec-Sobieszek4, Elżbieta Mądro5, Ewa Lech-Marańda5,6, Krzysztof Warzocha5, Jerome Tamburini7,8,9, Przemysław Juszczyński3 and Krzysztof Brzózka1
1Selvita S.A., Krakow, Poland
2Malopolska Centre of Biotechnology, Krakow, Poland
3Dept. of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
4Dept. of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
5Dept. of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
6Dept. of Hematology and Transfusion Medicine, Centre of Postgraduate Medical Education, Marymoncka, Warsaw, Poland
7Institut Cochin, Département Développement, Reproduction, Cancer, Paris, France
8Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
9Equipe Labellisée, Ligue Nationale Contre le Cancer (LNCC), Paris, France
*These authors have contributed equally to this work
Krzysztof Brzózka, email: [email protected]
Keywords: PIM kinase; FLT3 kinase; dual inhibitor; targeted therapy; AML
Received: March 06, 2017 Accepted: February 24, 2018 Published: March 30, 2018
Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is one of the most common genetic lesions in acute myeloid leukemia patients (AML). Although FLT3 tyrosine kinase inhibitors initially exhibit clinical activity, resistance to treatment inevitably occurs within months. PIM kinases are thought to be major drivers of the resistance phenotype and their inhibition in relapsed samples restores cell sensitivity to FLT3 inhibitors. Thus, simultaneous PIM and FLT3 inhibition represents a promising strategy in AML therapy. For such reasons, we have developed SEL24-B489 - a potent, dual PIM and FLT3-ITD inhibitor. SEL24-B489 exhibited significantly broader on-target activity in AML cell lines and primary AML blasts than selective FLT3-ITD or PIM inhibitors. SEL24-B489 also demonstrated marked activity in cells bearing FLT3 tyrosine kinase domain (TKD) mutations that lead to FLT3 inhibitor resistance. Moreover, SEL24-B489 inhibited the growth of a broad panel of AML cell lines in xenograft models with a clear pharmacodynamic-pharmacokinetic relationship. Taken together, our data highlight the unique dual activity of the SEL24-B489 that abrogates the activity of signaling circuits involved in proliferation, inhibition of apoptosis and protein translation/metabolism. These results underscore the therapeutic potential of the dual PIM/FLT3-ITD inhibitor for the treatment of AML.
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