Structure-affinity relationships of glutamine mimics incorporated into phosphopeptides targeted to the SH2 domain of signal transducer and activator of transcription 3.
Structure-affinity relationships of glutamine mimics incorporated into phosphopeptides targeted to the SH2 domain of signal transducer and activator of transcription 3.
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DOI：
10.1021/jm901105k
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发表时间：
2009-10-08
影响因子：
7.3
通讯作者：
McMurray, John S.
中科院分区：
文献类型：
--
作者：
Mandal, Pijus K.;Ren, Zhiyong;Chen, Xiaomin;Xiong, Chiyi;McMurray, John S.
在癌细胞中，信号转导子和转录激活子3（Stat 3）参与异常生长、存活、血管生成和侵袭信号，并且是抗癌药物设计的经验证的靶标。我们正在靶向其SH 2结构域，以防止与细胞因子和生长因子受体的对接以及随后的信号传导。识别序列pTyr-Xxx-Xxx-Gln的重要元件之一是谷氨酰胺。我们将新的Gln模拟物掺入到前导肽pCinn-Leu-Pro-Gln-NHBn中，发现线性、不受约束的侧链和羧酰胺对于高亲和力是必需的，并且苯甲酰胺可以被消除。用（R）-4-氨基戊酰胺或2-氨基乙基脲替代Gln-NHBn产生的抑制剂与先导化合物的抑制剂具有相同或更高的效力，如通过荧光偏振判断的（IC 50值分别为110和130 nM）。当Pro被cis-3，4-methanoproline取代时，谷氨酰胺模拟物（4 R，5S）-4-氨基-5-苄氧基己酰胺的IC 50为69 nM，是迄今报道的最高亲和力Stat 3抑制剂。
In cancer cells, signal transducer and activator of transcription 3 (Stat3) participates in aberrant growth, survival, angiogenesis, and invasion signals and is a validated target for anti-cancer drug design. We are targeting its SH2 domain to prevent docking to cytokine and growth factor receptors and subsequent signaling. One of the important elements of the recognition sequence, pTyr-Xxx-Xxx-Gln, is glutamine. We incorporated novel Gln mimics into a lead peptide, pCinn-Leu-Pro-Gln-NHBn, and found that a linear, unconstrained side chain and carboxamide are necessary for high affinity, and the benzamide can be eliminated. Replacement of Gln-NHBn with (R)-4-aminopentanamide or 2-aminoethylurea produced inhibitors with equal or greater potency than that of the lead, as judged by fluorescence polarization (IC50 values were 110 and 130 nM, respectively). When Pro was replaced with cis-3,4-methanoproline, the glutamine mimic, (4R,5S)-4-amino-5-benzyloxyhexanamide resulted in an IC50 of 69 nM, the highest affinity Stat3 inhibitor reported to date.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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影响因子：
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