PFI-1, a highly selective protein interaction inhibitor, targeting BET Bromodomains.
PFI-1, a highly selective protein interaction inhibitor, targeting BET Bromodomains.
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DOI：
10.1158/0008-5472.can-12-3292
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发表时间：
2013-06-01
期刊：
影响因子：
11.2
通讯作者：
Knapp S
中科院分区：
文献类型：
--
作者：
Picaud S;Da Costa D;Thanasopoulou A;Filippakopoulos P;Fish PV;Philpott M;Fedorov O;Brennan P;Bunnage ME;Owen DR;Bradner JE;Taniere P;O'Sullivan B;Müller S;Schwaller J;Stankovic T;Knapp S
溴和额外末端（BET）蛋白（BRD 2、BRD 3、BRD 4和BRDT）是有效表达几种生长促进和抗凋亡基因以及细胞周期进程所需的转录调节因子。BET蛋白通过其两个N-末端布罗莫结构域（BRD）募集到转录活性染色质，所述两个布罗莫结构域是特异性识别组蛋白H3和H4中的乙酰化赖氨酸残基的蛋白质相互作用模块。BET-组蛋白相互作用的抑制导致许多癌基因的转录下调，为癌症的治疗提供了新的药理学策略。在这里，我们提出了一种有效的和高选择性的二氢喹唑啉-2-酮抑制剂，PFI-1，有效地阻止与乙酰化组蛋白尾部的BET BRDs的相互作用。共晶体结构显示PFI-1作为乙酰基-赖氨酸（Kac）模拟物抑制剂有效地占据BRD 4和BRD 2中的Kac结合位点。PFI-1对白血病细胞系具有抗增殖作用，并有效地消除其克隆生长。敏感细胞系暴露于PFI-1导致G1期细胞周期阻滞、MYC表达下调以及诱导凋亡和诱导原代白血病母细胞分化。有趣的是，暴露于PFI-1的细胞显示出Aurora B激酶的显著下调，从而减弱Aurora底物H3 S10的磷酸化，为特异性抑制这种已确立的肿瘤学靶标提供了替代策略。
Bromo and extra terminal (BET) proteins (BRD2, BRD3, BRD4 and BRDT) are transcriptional regulators required for efficient expression of several growth promoting and anti-apoptotic genes as well as for cell cycle progression. BET proteins are recruited to transcriptionally active chromatin via their two N-terminal bromodomains (BRDs), a protein interaction module that specifically recognizes acetylated lysine residues in histones H3 and H4. Inhibition of the BET-histone interaction results in transcriptional down-regulation of a number of oncogenes providing a novel pharmacological strategy for the treatment of cancer. Here we present a potent and highly selective dihydroquinazoline-2-one inhibitor, PFI-1 that efficiently blocks the interaction of BET BRDs with acetylated histone tails. Co-crystal structures showed that PFI-1 acts as an acetyl-lysine (Kac) mimetic inhibitor efficiently occupying the Kac binding site in BRD4 and BRD2. PFI-1 has antiproliferative effects on leukaemic cell lines and efficiently abrogates their clonogenic growth. Exposure of sensitive cell lines with PFI-1 results in G1 cell cycle arrest, down-regulation of MYC expression as well as induction of apoptosis and induces differentiation of primary leukaemic blasts. Intriguingly, cells exposed to PFI-1 showed significant down-regulation of Aurora B kinase, thus attenuating phosphorylation of the Aurora substrate H3S10 providing an alternative strategy for the specific inhibition of this well established oncology target.