Oncotarget

Research Papers:

A novel dual panPIM/FLT3 inhibitor SEL24 exhibits broad therapeutic potential in acute myeloid leukemia

PDF  |  Full Text  |  Supplementary Files  |  How to cite

Oncotarget. 2018; 9:16917-16931. https://doi.org/10.18632/oncotarget.24747

Metrics: PDF 3102 views  |  Full Text 6086 views

Wojciech Czardybon1,*, Renata Windak1,*, Aniela GoÅ‚as1, MichaÅ‚ GaÅ‚Ä™zowski1, Aleksandra Sabiniarz1, Izabela Dolata1, Magdalena SalwiÅ„ska1, PaweÅ‚ Guzik1, Magdalena Zawadzka1, Ewelina Gabor-Worwa1, Bożena Winnik1, MaÅ‚gorzata Å»urawska1, Ewa KolasiÅ„ska1, Ewelina Wincza1, Marta Bugaj1, Monika Danielewicz1, Eliza Majewska1, Milena Mazan1, Grzegorz Dubin2, Monika Noyszewska-Kania3, Ewa JabÅ‚oÅ„ska3, Maciej SzydÅ‚owski3, Tomasz Sewastianik3, Bartosz PuÅ‚a5, Anna Szumera-Ciećkiewicz4, Monika Prochorec-Sobieszek4, Elżbieta MÄ…dro5, Ewa Lech-MaraÅ„da5,6, Krzysztof Warzocha5, Jerome Tamburini7,8,9, PrzemysÅ‚aw JuszczyÅ„ski3 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

Correspondence to:

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

ABSTRACT

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.