2. Academic Validation
  3. A novel, dual pan-PIM/FLT3 inhibitor SEL24 exhibits broad therapeutic potential in acute myeloid leukemia

A novel, dual pan-PIM/FLT3 inhibitor SEL24 exhibits broad therapeutic potential in acute myeloid leukemia

  • Oncotarget. 2018 Mar 30;9(24):16917-16931. doi: 10.18632/oncotarget.24747.
Wojciech Czardybon  # 1,  Renata Windak  # 1,  Aniela Gołas 1,  Michał Gałęzowski 1,  Aleksandra Sabiniarz 1,  Izabela Dolata 1,  Magdalena Salwińska 1,  Paweł Guzik 1,  Magdalena Zawadzka 1,  Ewelina Gabor-Worwa 1,  Bożena Winnik 1,  Małgorzata Żurawska 1,  Ewa Kolasińska 1,  Ewelina Wincza 1,  Marta Bugaj 1,  Monika Danielewicz 1,  Eliza Majewska 1,  Milena Mazan 1,  Grzegorz Dubin 2,  Monika Noyszewska-Kania 3,  Ewa Jabłońska 3,  Maciej Szydłowski 3,  Tomasz Sewastianik 3,  Bartosz Puła 4,  Anna Szumera-Ciećkiewicz 5,  Monika Prochorec-Sobieszek 5,  Elżbieta Mądro 4,  Ewa Lech-Marańda 4 6,  Krzysztof Warzocha 4,  Jerome Tamburini 7 8 9,  Przemysław Juszczyński 3,  Krzysztof Brzózka 1
Affiliations

Affiliations

  • 1 Selvita S.A., Krakow, Poland.
  • 2 Malopolska Centre of Biotechnology, Krakow, Poland.
  • 3 Dept. of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
  • 4 Dept. of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
  • 5 Dept. of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
  • 6 Dept. of Hematology and Transfusion Medicine, Centre of Postgraduate Medical Education, Marymoncka, Warsaw, Poland.
  • 7 Institut Cochin, Département Développement, Reproduction, Cancer, Paris, France.
  • 8 Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
  • 9 Equipe Labellisée, Ligue Nationale Contre le Cancer (LNCC), Paris, France.
  • # Contributed equally.
PMID: 29682194 DOI: 10.18632/oncotarget.24747
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.

Keywords

AML; FLT3 kinase; PIM kinase; dual inhibitor; targeted therapy.

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