Characterizing and Overriding the Structural Mechanism of the Quizartinib-Resistant FLT3 "Gatekeeper" F691L Mutation with PLX3397.
Characterizing and Overriding the Structural Mechanism of the Quizartinib-Resistant FLT3 "Gatekeeper" F691L Mutation with PLX3397.
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DOI：
10.1158/2159-8290.cd-15-0060
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发表时间：
2015-06
期刊：
影响因子：
28.2
通讯作者：
Shah NP
中科院分区：
文献类型：
--
作者：
Smith CC;Zhang C;Lin KC;Lasater EA;Zhang Y;Massi E;Damon LE;Pendleton M;Bashir A;Sebra R;Perl A;Kasarskis A;Shellooe R;Tsang G;Carias H;Powell B;Burton EA;Matusow B;Zhang J;Spevak W;Ibrahim PN;Le MH;Hsu HH;Habets G;West BL;Bollag G;Shah NP
酪氨酸激酶结构域突变是对用于治疗癌症的酪氨酸激酶抑制剂 (TKI)（包括 FLT3 抑制剂 quizartinib）获得性临床耐药性的常见原因。激酶“看门人”残基的突变控制着 ATP 结合位点附近的变构袋的进入，经常与 TKI 耐药有关。看门人突变介导的耐药性的分子基础尚不完全清楚。我们报告了 FLT3 与 TKI quizartinib 的第一个共晶结构，这表明 quizartinib 的结合依赖于与激活环中高度保守的 DFG 基序内的看门人 F691 残基和 F830 之间必需的边对面芳香族相互作用。这种依赖使得 quizartinib 极易受到看门人和激活环替代的影响，同时最大限度地减少其他地方突变的影响。此外，我们还发现了 PLX3397，一种新型 FLT3 抑制剂，由于其结合模式不太依赖与看门人位置的特定相互作用，因此保留了针对 F691L 突变体的活性。
Tyrosine kinase domain mutations are a common cause of acquired clinical resistance to tyrosine kinase inhibitors (TKIs) used to treat cancer, including the FLT3 inhibitor quizartinib. Mutation of kinase “gatekeeper” residues, which control access to an allosteric pocket adjacent to the ATP-binding site, have been frequently implicated in TKI resistance. The molecular underpinnings of gatekeeper mutation-mediated resistance are incompletely understood. We report the first co-crystal structure of FLT3 with the TKI quizartinib, which demonstrates that quizartinib binding relies on essential edge-to-face aromatic interactions with the gatekeeper F691 residue, and F830 within the highly conserved DFG motif in the activation loop. This reliance makes quizartinib critically vulnerable to gatekeeper and activation loop substitutions while minimizing the impact of mutations elsewhere. Moreover, we identify PLX3397, a novel FLT3 inhibitor that retains activity against the F691L mutant due to a binding mode that depends less vitally on specific interactions with the gatekeeper position.