Talman Virpi, Provenzani Riccardo, Boije af Gennäs Gustav, Tuominen Raimo K, Yli-Kauhaluoma Jari
*Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, P.O. Box 56 (Viikinkaari 5 E), University of Helsinki, 00014 Helsinki, Finland.
†Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, P.O. Box 56 (Viikinkaari 5 E), University of Helsinki, 00014 Helsinki, Finland.
Biochem Soc Trans. 2014 Dec;42(6):1543-9. doi: 10.1042/BST20140181.
Protein kinase C (PKC) is a serine/threonine kinase belonging to the AGC family. PKC isoenzymes are activated by phospholipid-derived second messengers, transmit their signal by phosphorylating specific substrates and play a pivotal role in the regulation of various cell functions, including metabolism, growth, differentiation and apoptosis. Therefore they represent an interesting molecular target for the treatment of several diseases, such as cancer and Alzheimer's disease. Adopting a structure-based approach on the crystal structure of the PKCδ C1B domain, our team has developed isophthalic acid derivatives that are able to modify PKC functions by binding to the C1 domain of the enzyme. Bis[3-(trifluoromethyl)benzyl] 5-(hydroxymethyl)isophthalate (HMI-1a3) and bis(1-ethylpentyl) 5-(hydroxymethyl)isophthalate (HMI-1b11) were selected from a set of compounds for further studies due to their high affinity for the C1 domains of PKCα and PKCδ. HMI-1a3 showed marked antiproliferative activity in HeLa cells whereas HMI-1b11 induced differentiation and supported neurite growth in SH-SY5Y cells. Our aim in the future is to improve the selectivity and potency of isophthalate derivatives, to clarify their mechanism of action in the cellular environment and to assess their efficacy in cell-based and in vivo disease models. HMI-1a3 has already been selected for a further project and redesigned to function as a probe immobilized on an affinity chromatography column. It will be used to identify cellular target proteins from cell lysates, providing new insights into the mechanism of action of HMI-1a3.
蛋白激酶C（PKC）是一种属于AGC家族的丝氨酸/苏氨酸激酶。PKC同工酶由磷脂衍生的第二信使激活，通过磷酸化特定底物来传递信号，并在调节各种细胞功能（包括代谢、生长、分化和凋亡）中发挥关键作用。因此，它们是治疗多种疾病（如癌症和阿尔茨海默病）的一个有趣的分子靶点。基于PKCδ C1B结构域的晶体结构采用基于结构的方法，我们的团队开发了能够通过与该酶的C1结构域结合来改变PKC功能的间苯二甲酸衍生物。双[3-（三氟甲基）苄基] 5-（羟甲基）间苯二甲酸酯（HMI-1a3）和双（1-乙基戊基）5-（羟甲基）间苯二甲酸酯（HMI-1b11）由于对PKCα和PKCδ的C1结构域具有高亲和力，从一组化合物中被选出来进行进一步研究。HMI-1a3在HeLa细胞中显示出显著的抗增殖活性，而HMI-1b11在SH-SY5Y细胞中诱导分化并支持神经突生长。我们未来的目标是提高间苯二甲酸衍生物的选择性和效力，阐明它们在细胞环境中的作用机制，并评估它们在基于细胞和体内疾病模型中的疗效。HMI-1a3已被选入一个进一步的项目，并被重新设计用作固定在亲和色谱柱上的探针。它将用于从细胞裂解物中鉴定细胞靶蛋白，为HMI-1a3的作用机制提供新的见解。
