Weisberg Ellen, Roesel Johannes, Furet Pascal, Bold Guido, Imbach Patricia, Flörsheimer Andreas, Caravatti Georgio, Jiang Jingrui, Manley Paul, Ray Arghya, Griffin James D
Department of Medical Oncology/Hematologic Neoplasia, Dana Farber Cancer Institute, Boston, MA, USA.
Genes Cancer. 2010 Oct;1(10):1021-32. doi: 10.1177/1947601910396505.
Constitutively activated mutant FLT3 has emerged as a promising target for therapy for the subpopulation of acute myeloid leukemia (AML) patients who harbor it. The small molecule inhibitor, PKC412, targets mutant FLT3 and is currently in late-stage clinical trials. However, the identification of PKC412-resistant leukemic blast cells in the bone marrow of AML patients has propelled the development of novel and structurally distinct FLT3 inhibitors that have the potential to override drug resistance and more efficiently prevent disease progression or recurrence. Here, we present the novel first-generation "type II" FLT3 inhibitors, AFG206, AFG210, and AHL196, and the second-generation "type II" derivatives and AST487 analogs, AUZ454 and ATH686. All agents potently and selectively target mutant FLT3 protein kinase activity and inhibit the proliferation of cells harboring FLT3 mutants via induction of apoptosis and cell cycle inhibition. Cross-resistance between "type I" inhibitors, PKC412 and AAE871, was demonstrated. While cross-resistance was also observed between "type I" and first-generation "type II" FLT3 inhibitors, the high potency of the second-generation "type II" inhibitors was sufficient to potently kill "type I" inhibitor-resistant mutant FLT3-expressing cells. The increased potency observed for the second-generation "type II" inhibitors was observed to be due to an improved interaction with the ATP pocket of FLT3, specifically associated with introduction of a piperazine moiety and placement of an amino group in position 2 of the pyrimidine ring. Thus, we present 2 structurally novel classes of FLT3 inhibitors characterized by high selectivity and potency toward mutant FLT3 as a molecular target. In addition, presentation of the antileukemic effects of "type II" inhibitors, such as AUZ454 and ATH686, highlights a new class of highly potent FLT3 inhibitors able to override drug resistance that less potent "type I" inhibitors and "type II" first-generation FLT3 inhibitors cannot.
组成型激活的突变型FLT3已成为携带该突变的急性髓系白血病（AML）患者亚群治疗的一个有前景的靶点。小分子抑制剂PKC412靶向突变型FLT3，目前正处于后期临床试验阶段。然而，在AML患者骨髓中鉴定出对PKC412耐药的白血病原始细胞，推动了新型且结构不同的FLT3抑制剂的研发，这些抑制剂有可能克服耐药性并更有效地预防疾病进展或复发。在此，我们展示了新型第一代“II型”FLT3抑制剂AFG206、AFG210和AHL196，以及第二代“II型”衍生物和AST487类似物AUZ454和ATH686。所有药物均能有效且选择性地靶向突变型FLT3蛋白激酶活性，并通过诱导凋亡和抑制细胞周期来抑制携带FLT3突变的细胞增殖。已证实“I型”抑制剂PKC412和AAE871之间存在交叉耐药性。虽然在“I型”和第一代“II型”FLT3抑制剂之间也观察到了交叉耐药性，但第二代“II型”抑制剂的高效力足以有效杀死表达对“I型”抑制剂耐药的突变型FLT3的细胞。观察到第二代“II型”抑制剂效力增强是由于与FLT3的ATP口袋的相互作用得到改善，这具体与引入哌嗪部分以及在嘧啶环的2位放置氨基有关。因此，我们展示了两类结构新颖的FLT3抑制剂，其特征是对作为分子靶点的突变型FLT3具有高选择性和高效力。此外，展示“II型”抑制剂如AUZ454和ATH686的抗白血病作用，突出了一类新型的高效FLT3抑制剂，它们能够克服耐药性，而效力较低的“I型”抑制剂和第一代“II型”FLT3抑制剂则无法做到。
