新型Pin1小分子抑制剂设计、合成和抗肿瘤活性研究

Pin1 is a promising anticancer therapeutic target with an unique mechanism.Pin1 promotes oncogenesis by activating numerous oncogenes and by inactivating many tumor suppressors associated with different signalling pathways.Therefore, Pin1 inhibitors can simultaneously inhibit several oncogenic pathways and thus provide opportunities for the anticancer treatments.Based on the binding modes of the quinazoline and benzophenone Pin1 inhibitors developed in our early efforts, novel chemical entities containg thiazolopyrimidinone, biaryl and thiazoloaryl ether scaffolds are designed by performing scaffold hopping.The inhibitory activities against Pin1 and tumor cells and pharmacokinetic properties of target molecules are evaluated so as to discover novel Pin1 inhibitors with potent antitumor activities. More importantly, in this proposal the optimization of the leads are guided by the thermodynamic study of the binding process since the binding affinity is closely related to the free energy, enthalpy and entropy.In combination with the molecular modeling,the relationship between the thermodynamic parameters and structures of the representative compounds are employed to disclose the nature of binding force in the microscopic level.

Pin1酶作为新作用机制抗癌药物靶标，其抑制剂可阻断多个癌信号传导途径，现今尚无抑制剂进入临床研究。基于前一国家自科基金发现的喹唑啉和二苯酮类Pin1抑制剂，本项目采用基于结构的分子设计和骨架迁越策略，设计合成噻唑嘧啶酮、嘧啶联苯和噻唑芳基醚类新结构类型化合物。经测定酶抑制活性、抑制肿瘤细胞生长活性和过膜性质评价，获得具有Pin1抑制作用的高质量的新型抗肿瘤药物先导结构。本项目的另一特色是将热力学研究用于先导结构的演化和优化，将活性分子同Pin1酶的结合强度与相互作用过程中产生的自由能、焓和熵变相结合，指导分子设计。测定代表性化合物的热力学参数，结合分子模拟，研究Ki、ΔG、ΔH和ΔS与结构变换的关系，揭示抑制剂与Pin1相互作用的微观本质，在深层次上挖掘分子设计的内涵。

Pin1是一种肽脯氨酰异构酶，在肿瘤的发生和发展中有重要作用。Pin1抑制剂是潜在的抗肿瘤药物，经过多年的探索，取得了一定的研究进展，但尚未该类抑制剂作为抗肿瘤药物上市。本项目是在课题组前期工作的基础上，采用基于结构的药物分子设计策略，设计合成了3种结构类型化合物近200个，获得了对Pin1具有抑制活性的2种结构类型的先导结构，丰富了Pin1抑制剂的构效关系，为进一步结构优化奠定了扎实的基础。本课题还采用ITC方法测定了文献报道的Pin1抑制剂的热力学结合常数，为进一步采用热力学方法研究Pin1抑制剂提供了方法学基础。本项目采用结构生物学方法，获得了新结构Pin1小分子抑制剂与Pin1复合物的晶体结构，揭示了其独特的结合模式，为进一步设计全新的Pin1小分子抑制剂提供了新的思路。本课题还发展了一种新的含有噻唑环的二芳基胺的合成方法，也为合成该结构类型Pin1抑制剂提供了合成基础。本项目的实施，为开发Pin1小分子抑制剂成为抗肿瘤药物提供了重要的研究思路，奠定了重要的物质基础。发表研究论文3篇。