Czardybon Wojciech, Windak Renata, Gołas Aniela, Gałęzowski Michał, Sabiniarz Aleksandra, Dolata Izabela, Salwińska Magdalena, Guzik Paweł, Zawadzka Magdalena, Gabor-Worwa Ewelina, Winnik Bożena, Żurawska Małgorzata, Kolasińska Ewa, Wincza Ewelina, Bugaj Marta, Danielewicz Monika, Majewska Eliza, Mazan Milena, Dubin Grzegorz, Noyszewska-Kania Monika, Jabłońska Ewa, Szydłowski Maciej, Sewastianik Tomasz, Puła Bartosz, Szumera-Ciećkiewicz Anna, Prochorec-Sobieszek Monika, Mądro Elżbieta, Lech-Marańda Ewa, Warzocha Krzysztof, Tamburini Jerome, Juszczyński Przemysław, Brzózka Krzysztof
Selvita S.A., Krakow, Poland.
Malopolska Centre of Biotechnology, Krakow, Poland.
Oncotarget. 2018 Mar 30;9(24):16917-16931. doi: 10.18632/oncotarget.24747.
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.
Fms样酪氨酸激酶3内部串联重复（FLT3-ITD）是急性髓系白血病患者（AML）中最常见的基因病变之一。尽管FLT3酪氨酸激酶抑制剂最初表现出临床活性，但数月内不可避免地会出现治疗耐药性。PIM激酶被认为是耐药表型的主要驱动因素，在复发样本中抑制它们可恢复细胞对FLT3抑制剂的敏感性。因此，同时抑制PIM和FLT3是AML治疗中一种有前景的策略。基于这些原因，我们开发了SEL24-B489——一种强效的双靶点PIM和FLT3-ITD抑制剂。与选择性FLT3-ITD或PIM抑制剂相比，SEL24-B489在AML细胞系和原发性AML原始细胞中表现出显著更广泛的靶向活性。SEL24-B489在携带导致FLT3抑制剂耐药的FLT3酪氨酸激酶结构域（TKD）突变的细胞中也显示出显著活性。此外，SEL24-B489在异种移植模型中抑制了多种AML细胞系的生长，具有明确的药效学-药代动力学关系。综上所述，我们的数据突出了SEL24-B489独特的双重活性，它可消除参与增殖、抑制细胞凋亡以及蛋白质翻译/代谢的信号通路的活性。这些结果强调了双靶点PIM/FLT3-ITD抑制剂在AML治疗中的潜在治疗价值。
