Design, Synthesis, and Biological Activity of Isophthalic Acid Derivatives Targeted to the C1 Domain of Protein Kinase C
Design, Synthesis, and Biological Activity of Isophthalic Acid Derivatives Targeted to the C1 Domain of Protein Kinase C
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DOI：
10.1021/jm900229p
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发表时间：
2009-07-09
影响因子：
7.3
通讯作者：
Yli-Kauhaluoma, Jari
中科院分区：
文献类型：
--
作者：
af Gennas, Gustav Boije;Talman, Virpi;Yli-Kauhaluoma, Jari
蛋白激酶C（PKC）是一种广泛研究的治疗癌症和其他疾病的分子靶点。我们已经接近的问题，修改PKC功能，通过靶向的C1结构域的调节区的酶。利用PKC δ C1 b结构域的X射线晶体结构，我们发现了可以作为潜在C1结构域配体的5-（羟甲基）戊酸二烷基酯的方便合成衍生物。结构-活性研究证实，通过建模预测的重要官能团对于与C1结构域的结合是必不可少的，并且这些基团的修饰减少了结合。最有前途的化合物能够在200-900 nM范围内的Ki值下从PKC α和δ中取代放射性标记的佛波酯（[H-3]PDBu）。此外，活性异丁酸酯衍生物可以通过诱导PKC依赖性ERK磷酸化或通过抑制佛波醇诱导的ERK磷酸化来修饰活细胞中的PKC活化。最后，我们在此首次报告。因此，本发明人认识到，阿糖胞苷酸衍生物代表了一组有吸引力的新型C1结构域配体，其可用作研究工具或进一步修饰用于潜在的药物开发。
Protein kinase C (PKC) is a widely studied molecular target for the treatment of cancer and other diseases. We have approached the issue of modifying PKC function by targeting the C1 domain in the regulatory region of the enzyme. Using the X-ray crystal structure of the PKC delta C1b domain, we have discovered conveniently synthesizable derivatives of dialkyl 5-(hydroxymethyl)isophthalate that can act as potential C1 domain ligands. Structure-activity studies confirmed that the important functional groups predicted by modeling were indispensable for binding to the C1 domain and that the modifications of these groups diminished binding. The most promising compounds were able to displace radiolabeled phorbol ester ([H-3]PDBu) from PKC alpha and delta at K-i values in the range of 200-900 nM. Furthermore, the active isophthalate derivatives could modify PKC activation in living cells either by inducing PKC-dependent ERK phosphorylation or by inhibiting phorbol-induced ERK phosphorylation. In conclusion, we report here, for the first time. that derivatives of isophthalic acid represent an attractive novel group of C1 domain ligands that can be used as research tools or further modified for potential drug development.