State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
Theranostics. 2021 Jan 1;11(1):93-106. doi: 10.7150/thno.46593. eCollection 2021.
Acute myeloid leukemia (AML) is a common type of haematological malignancy. Several studies have shown that neoplasia in AML is enhanced by tyrosine kinase pathways. Recently, given that aberrant activation of Fms-like tyrosine receptor kinase 3 (FLT3) acts as a critical survival signal for cancer cells in 20‒30% patients with AML, inhibition of FLT3 may be a potential therapeutic strategy. Therefore, we identified LT-171-861, a novel kinase inhibitor with remarkable inhibitory activity against FLT3, in preclinical models of AML. We determined the inhibitory effects of LT-171-861 using AML cell lines and transformed BaF3 cells. Target engagement assays were used to verify the interaction between LT-171-861 and FLT3. Finally, a subcutaneous model and a bone marrow engrafted model were used to evaluate the antitumor effects of LT‑171‑861 . Our data demonstrated that LT-171-861 had high affinity for FLT3 protein. We also showed that LT-171-861 had an inhibitory effect on FLT3 mutants in cellular assays. Moreover, LT-171-861 had a growth-inhibitory effect on human AML cell lines harboring FLT3 internal tandem duplications (FLT3-ITD) such as FLT3-D835Y, FLT3‑ITD-N676D, FLT3-ITD-D835Y, FLT3-ITD-F691L, FLT3-ITD-Y842C and AML blasts from patients with FLT3-ITD. Furthermore, LT-171-861 showed potent antileukemic efficacy against AML cells. We also show the efficacy of LT‑171-861 in a subcutaneous implantation model and a bone marrow engrafted model , where administration of LT-171-861 led to almost complete tumor regression and increased survival. Overall, this study not only identifies LT-171-861 as a potent FLT3 inhibitor, but also provides a rationale for the upcoming clinical trial of LT-171-861 in patients with AML and FLT3-ITD mutations.
急性髓系白血病（AML）是一种常见的血液系统恶性肿瘤。多项研究表明，酪氨酸激酶途径增强了 AML 中的肿瘤发生。最近，由于异常激活 Fms 样酪氨酸激酶 3（FLT3）作为 20%至 30% AML 患者癌细胞的关键存活信号，抑制 FLT3 可能是一种潜在的治疗策略。因此，我们在 AML 的临床前模型中鉴定出 LT-171-861，这是一种对 FLT3 具有显著抑制活性的新型激酶抑制剂。我们使用 AML 细胞系和转化的 BaF3 细胞来确定 LT-171-861 的抑制作用。靶标结合试验用于验证 LT-171-861 与 FLT3 的相互作用。最后，我们使用皮下模型和骨髓植入模型来评估 LT-171-861 的抗肿瘤作用。我们的数据表明，LT-171-861 对 FLT3 蛋白具有高亲和力。我们还表明，LT-171-861 在细胞试验中对 FLT3 突变体具有抑制作用。此外，LT-171-861 对携带 FLT3 内部串联重复（FLT3-ITD）的人 AML 细胞系具有生长抑制作用，例如 FLT3-D835Y、FLT3-ITD-N676D、FLT3-ITD-D835Y、FLT3-ITD-F691L、FLT3-ITD-Y842C 和 FLT3-ITD 患者的 AML blasts。此外，LT-171-861 对 AML 细胞具有强大的抗白血病疗效。我们还展示了 LT-171-861 在皮下植入模型和骨髓植入模型中的疗效，其中 LT-171-861 的给药导致几乎完全的肿瘤消退和延长的生存。总的来说，这项研究不仅鉴定出 LT-171-861 是一种有效的 FLT3 抑制剂，而且为即将进行的 LT-171-861 在 AML 和 FLT3-ITD 突变患者中的临床试验提供了依据。
