FLT3 的激活突变会导致急性髓系白血病 (AML) 患者的造血干细胞和祖细胞 (HSC/Ps) 生长和生存失调，从而导致总体生存率较差。接受针对突变 FLT3 的研究药物（包括 Quizartinib 和 Crenolanib）治疗的 AML 患者会对这些药物产生耐药性。耐药性的产生很大程度上是由于同时发生的突变的获得和额外生存途径的激活，以及额外FLT3突变的出现。尽管 FLT3 突变的发生率很高且在 AML 中具有临床意义，但可用的靶向治疗选择很少。我们已经鉴定出 2 种新型基于烟酰胺的 FLT3 抑制剂（HSN608 和 HSN748），它们以亚纳摩尔浓度靶向 FLT3 突变，并且对 FLT3 的耐药二次突变有效。这些化合物在耐药性 AML、复发/难治性 AML 以及携带 TET2 和 FLT3ITD 表观遗传突变组合的 AML 中显示出针对 FLT3ITD 的抗白血病活性。我们证明，HSN748 在体内对 FLT3ITD 的抑制活性方面优于 FDA 批准的 FLT3 抑制剂 Gilteritinib。

Activating mutations of FLT3 contribute to deregulated hematopoietic stem and progenitor cell (HSC/Ps) growth and survival in patients with acute myeloid leukemia (AML), leading to poor overall survival. AML patients treated with investigational drugs targeting mutant FLT3, including Quizartinib and Crenolanib, develop resistance to these drugs. Development of resistance is largely due to acquisition of cooccurring mutations and activation of additional survival pathways, as well as emergence of additional FLT3 mutations. Despite the high prevalence of FLT3 mutations and their clinical significance in AML, there are few targeted therapeutic options available. We have identified 2 novel nicotinamide-based FLT3 inhibitors (HSN608 and HSN748) that target FLT3 mutations at subnanomolar concentrations and are potently effective against drug-resistant secondary mutations of FLT3. These compounds show antileukemic activity against FLT3ITD in drug-resistant AML, relapsed/refractory AML, and in AML bearing a combination of epigenetic mutations of TET2 along with FLT3ITD. We demonstrate that HSN748 outperformed the FDA-approved FLT3 inhibitor Gilteritinib in terms of inhibitory activity against FLT3ITD in vivo.