The Irreversible FLT3 Inhibitor FF-10101 Is Active Against a Diversity of FLT3 Inhibitor Resistance Mechanisms.
The Irreversible FLT3 Inhibitor FF-10101 Is Active Against a Diversity of FLT3 Inhibitor Resistance Mechanisms.
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DOI：
10.1158/1535-7163.mct-21-0317
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发表时间：
2022-05-04
影响因子：
5.7
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中科院分区：
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经过多年的开发，小分子FLT 3抑制剂最近改善了FLT 3突变型急性髓性白血病（AML）患者的临床结局，但耐药性仍然是一个重要的临床问题。FF-10101是FLT 3的第一种不可逆的共价抑制剂，先前已显示出对FLT 3酪氨酸激酶抑制剂耐药引起的FLT 3 F691 L和D835突变的活性。我们报告说，FF-10101也对一组扩大的临床鉴定的FLT 3突变具有活性，这些突变与对其他FLT 3抑制剂的耐药性相关。我们还证明，FF-10101可以潜在地解决与骨髓微环境中存在的生长因子相关的耐药机制，但容易在共价FLT 3结合所需的氨基酸C695处发生突变。这些数据表明，FF-10101具有良好的耐药性特征，当用于FLT 3突变型AML患者时，可能有助于改善单药疗效。
Small-molecule FLT3 inhibitors have recently improved clinical outcomes for patients with FLT3-mutant acute myeloid leukemia (AML) after many years of development, but resistance remains an important clinical problem. FF-10101 is the first irreversible, covalent inhibitor of FLT3 which has previously shown activity against FLT3 tyrosine kinase inhibitor resistance-causing FLT3 F691L and D835 mutations. We report that FF-10101 is also active against an expanded panel of clinically identified FLT3 mutations associated with resistance to other FLT3 inhibitors. We also demonstrate that FF-10101 can potentially address resistance mechanisms associated with growth factors present in the bone marrow microenvironment but is vulnerable to mutation at C695, the amino acid required for covalent FLT3 binding. These data suggest that FF-10101 possesses a favorable resistance profile that may contribute to improved single agent efficacy when used in patients with FLT3-mutant AML.