Internal tandem duplication (ITD) or tyrosine kinase domain mutations of FLT3 is the most frequent genetic alteration in acute myelogenous leukemia (AML) and are associated with poor disease outcome. Despite considerable efforts to develop single-target FLT3 drugs, so far, the most promising clinical response has been achieved using the multikinase inhibitor midostaurin. Here, we explore the activity of the indolocarbazole EC-70124, from the same chemical space as midostaurin, in preclinical models of AML, focusing on those bearing FLT3-ITD mutations. EC-70124 potently inhibits wild-type and mutant FLT3, and also other important kinases such as PIM kinases. EC-70124 inhibits proliferation of AML cell lines, inducing cell-cycle arrest and apoptosis. EC-70124 is orally bioavailable and displays higher metabolic stability and lower human protein plasma binding compared with midostaurin. Both in vitro and in vivo pharmacodynamic analyses demonstrate inhibition of FLT3-STAT5, Akt-mTOR-S6, and PIM-BAD pathways. Oral administration of EC-70124 in FLT3-ITD xenograft models demonstrates high efficacy, reaching complete tumor regression. Ex vivo, EC-70124 impaired cell viability in leukemic blasts, especially from FLT3-ITD patients. Our results demonstrate the ability of EC-70124 to reduce proliferation and induce cell death in AML cell lines, patient-derived leukemic blast and xenograft animal models, reaching best results in FLT3 mutants that carry other molecular pathways' alterations. Thus, its unique inhibition profile warrants EC-70124 as a promising agent for AML treatment based on its ability to interfere the complex oncogenic events activated in AML at several levels. Mol Cancer Ther; 17(3); 614–24. ©2018 AACR.

中文翻译：

---

EC-70124 抑制 FLT3 和 PIM 激酶在急性髓系白血病的临床前模型中发挥有效作用

FLT3 的内部串联重复 (ITD) 或酪氨酸激酶结构域突变是急性髓性白血病 (AML) 中最常见的基因改变，并且与不良的疾病结果相关。尽管在开发单靶点 FLT3 药物方面付出了相当大的努力，但迄今为止，使用多激酶抑制剂 Midostaurin 已经取得了最有希望的临床反应。在这里，我们在 AML 的临床前模型中探索了吲哚并咔唑 EC-70124 的活性，它来自与米司他林相同的化学空间，重点是那些带有 FLT3-ITD 突变的模型。EC-70124 有效抑制野生型和突变型 FLT3，以及其他重要的激酶，如 PIM 激酶。EC-70124 抑制 AML 细胞系的增殖，诱导细胞周期停滞和细胞凋亡。EC-70124 具有口服生物利用度，与midostaurin 相比，具有更高的代谢稳定性和更低的人体蛋白质血浆结合。体外和体内药效学分析均表明对 FLT3-STAT5、Akt-mTOR-S6 和 PIM-BAD 通路的抑制。在 FLT3-ITD 异种移植模型中口服 EC-70124 显示出高效，达到完全肿瘤消退。在体外，EC-70124 损害了白血病原始细胞的细胞活力，尤其是来自 FLT3-ITD 患者。我们的结果证明了 EC-70124 在 AML 细胞系、源自患者的白血病母细胞和异种移植动物模型中减少增殖和诱导细胞死亡的能力，在携带其他分子途径改变的 FLT3 突变体中达到最佳结果。因此，其独特的抑制特性保证 EC-70124 作为 AML 治疗的有前途的药物，因为它能够在多个水平干扰 AML 中激活的复杂致癌事件。摩尔癌症治疗; 17(3); 614-24。©2018 AACR。