高选择性蛋白酪氨酸磷酸酶SHP2抑制剂的研究

Src homology 2 domain-containing phosphatase 2 (SHP-2) plays an important role in mediating multiple downstream biological responses, such as proliferation and/or survival, adhesion, and migration.The over-expression of SHP2 is correlated closely with many cancers and therefore has becoming new target for anticancer drugs. Studies on selective SHP2 inhibitors may generate leading compounds for anticancer drug research program and provide specific substrates for studies on the bio-function and mechanism of SHP2 in cell signaling patgway. .In our group, over 150 compounds have been synthesized and some promising lead molecules have been screened from enzymetic assay as SHP2 inhibitor. Those potential lead compounds having novel structure and have submitted for IP protection (No. 201110364762.6). However, the issue arises from the current leads including selectivity between PTP protein groups of SHP2, PTP1B and others, which have high homology and may cause side effects from non-selective inhibitors. Therefore, further progress is expected on issues of selectivity and bioavailability associated with targeting SHP2 for therapeutic development. .The objective of the this proposal is to design and create highly selective SHP2 inhibitors by conduct a 3D-QSAR study from our lead molecules. Through a CADD approach, our final goal is to design and synthesize highly potent and selective SHP2 inhibitors as promising anticancer drug candidate.

蛋白酪氨酸磷酸酶SHP2在细胞生长、增殖、分化等多种活动中具有重要作用。其过度表达或突变与多种癌症相关。已成为新的抗癌药物靶标。选择性SHP2抑制剂的研究将为新型抗癌药提供先导物，同时能为研究SHP2 在细胞信号转导中的生物功能及作用机制提供特异性底物。本课题组通过前期工作，发现了结构全新的先导物，并申报了发明专利（201110364762.6）。由于SHP2 与同家族的其它酶（SHP1、PTP1B）有很高的同源性，因此，先导物的"选择性"还不理想，需要进一步研究提高。该项目，将在已有工作的基础上，对前期已经合成的且已经获得活性数据的化合物进行三维定量构效关系研究，建立不同靶标药效团模型，研究其差异性，总结规律，指导对先导物进行结构优化及分子设计并对设计的目标化合物进行合成及活性筛选，获得活性强、选择性高的SHP2抑制剂。 为新型抗癌药研究提供先导化合物。

本项目用高能分子动力学模拟的方法，即在SHP2蛋白分子动力学模拟体系中增加环境动能的方法，对SHP2如何调节构象使其暴露活性催化区域进行了观察，确定对调节构象变化起重要作用的关键残基群。通过对比关键残基群的二面角分布，RMSF高低和相互位置关系改变，从理论上寻找对构象调节起关键作用的残基作为新的SHP2抑制剂的结合位点。利用该结合位点为对接口袋进行高通量虚拟筛选，结构优化并合成得到有潜在选择性抑制作用的化合物。通过高能分子动力学模拟、酶活性实验，细胞生长实验等验证了该类化合物的结合模式和生物活性。.本项目首次运用原创的高能分子动力学模拟发现了SHP2蛋白暴露活性区域转化为活性构象的机理和方式，并且从理论上找到了可以抑制SHP2变构的结合位点Site K。经过一系列筛选和优化，合成得到了具有选择性的化合物RP-9。RP-9能抑制SHP2酶的活性，对SHP2抑制的IC50为1.5uM，对SHP1的选择性为18倍。分子动力学模拟和高能分子动力学表明，该化合物可以稳定结合在Site K结合位点，抑制SHP2变构，该位点也是首次用高能分子动力学理论获得。理论探索加之实验结论会对今后设计并合成更为有效的选择性SHP2抑制剂提供依据。

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