基于片段的药物设计方法研发抗肿瘤药物HSP90抑制剂

Heat Shock Protein(HSP) 90 is a very important chaperone in cells. It assists the mutant or unstable proteins to fold properly to excute their functions. Inhibition of the HSP90 will affect many client proteins of HSP90, including many oncogenic proteins, such as Raf,HER2,AKT etc. Then the inhibitors of HSP90 is thought to have a complex role in signaling pathways involving its cilent proteins and will be a better way to tackle the cancer, since the development of cancer is also a multi-factor complex event. In present application, we utilize the Fragment-Based Drug Discovery(FBDD) method to develop the HSP90 inhibitors as anticancer drug. The FBDD method combines the advantages of random screening and rational structure-based drug design. With the help of many biophysical technologies, such as NMR, X-ray, SPR, ITC etc., the FBDD method can be used to quickly find the novel fragments binding to the protein targets even only screening thousands of fragments, which is mainly due to its better chemical space coverage. Fragments are usually thought to have better ligand efficiency and suitable to optimize the drugabbility that is the barrier of modern drug discovery. Through this project, we will not only develop the novel and patentable HSP90 inhibitors to study the mechanism of HSP90 in cancer cells, but also further strength our FBDD platform to serve as a basis for other drug discovery projects.

HSP90是细胞内重要的分子伴侣蛋白，帮助许多突变或构象不稳定的蛋白进行正确折叠，从而发挥客户蛋白的生物功能。对HSP90的抑制可以调控多个癌基因的蛋白活性构象，从而达到"一靶多标"的抗肿瘤效果。本项目采用基于片段的药物设计方法开展HSP90抑制剂的研究。该方法集合随机筛选和基于结构理性设计的长处，具有快速发现新颖结构片段、快速优化分子，成药性优化空间大等优点。在研发HSP90抑制剂的过程中，将逐步完善片段药物发现平台，扩充现有片段库，建立多种生物物理的弱结合片段的检测方法，建立基于X射线结构生物学的片段优化技术。一方面获得高活性的HSP90抑制剂为抗肿瘤研发提供新型靶向抑制剂，从而深入探索HSP90的抗肿瘤机制；另一方面也建立片段药物发现平台，为其它靶点的创新药物及探针分子设计提供基础。

通过本课题的资助，经4年的努力，自评价认为较好地完成了预期设定的研究目标。研究中主要取得了两类成果，一是完善了我们的FBDD的研究平台，为整个药物研究所和本团队提供了重要的研究手段，可以作为高通量筛选发现苗头化合物的重要补充。通过这几年的不断积累和建设，目前，我们已拥有片段分子1500余个，建成了基于NMR技术、质谱技术、Thermoshift技术等多种生物物理检测方法，目前已开展10余个靶点的片段药物发现工作，其中BRD4抑制剂的研究就采用了该平台，也取得了非常优异的成绩，证明了平台的可靠性和高效性。另外一个方面是提供了新颖结构的HSP90抑制剂，对于二酚类结构的优化获得了一系列高活性的化合物，通过成药性评价，我们确定其中化合物FS-93和FS-108具有进一步开发的价值。两个化合物的分子活性~10nM,细胞活性也优于<20nM。我们对其也开展了体内药效学评价和靶点功能机制研究，目前正进行深入的开发工作。综上所述，我们通过本课题的资助，不但提供了良好的药物发现平台，也顺利获得高活性化合物进行药物研发，顺利完成既定研究任务，为国家创新药物研究做出一定的贡献。

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