靶向肿瘤代谢新型PHGDH抑制剂的设计合成及生物活性评价

Targeting cancer metabolism is an important strategy and challenge for drug discovery. Targeting phosphoglycerate dehydrogenase (PHGDH), inhibiting de novo serine synthesis pathway, and then regulating tumor metabolism are current frontier hot topics of anti-tumor development. In our previous study, a novel PHGDH inhibitor (GDD-101) was discovered by high-throughput screening. Then, compound GDD-102 with further enhanced activity was obtained by using a high-efficient synthesis strategy. On the basis of these previous research, this project intends to carry out the following work : (1) Systematic structural optimization to obtain active molecules with strong inhibitory activity and high selectivity; (2) Systematic bioactivity evaluation to obtain lead compounds with good drug-like properties and clear molecular mechanism; (3) Investigating the effects of lead compounds on drug-resistant tumor cells and animal models with PHGDH overexpression. The successful implementation of this project has important scientific significance and broad application prospects, which not only promote the research of PHGDH inhibitors and their biological functions, but also accelerate the development of anti-tumor drugs in the field of tumor metabolism.

靶向肿瘤代谢是新药发现的重要策略和挑战领域，靶向磷酸甘油酸脱氢酶（PHGDH）、抑制丝氨酸从头合成途径、进而调节肿瘤代谢是当前抗肿瘤研发的前沿热点。我们前期利用高通量筛选发现了一类结构新颖的PHGDH抑制剂GDD-101，采用高效合成策略进行优化获得了活性进一步提高的化合物GDD-102。本项目拟在前期研究成果的基础上开展如下工作：（1）进行系统结构优化，获得抑制活性强、选择性高的活性分子；（2）开展系统的生物活性评价，获得类药性好的先导化合物，并阐明其分子作用机制；（3）探讨先导化合物对PHGDH高表达的耐药肿瘤细胞及动物模型的影响。本项目的顺利开展不仅可以促进PHGDH抑制剂及其生物学功能的研究，也将加快肿瘤代谢领域抗肿瘤药物研发，具有重要的科学意义和广阔的应用前景。

肿瘤的难治愈性很大程度上是由于肿瘤细胞内基因突变和代谢通路改变的复杂性。丝氨酸合成通路（Serine Synthetic Pathway，SSP）作为糖酵解途径的一个重要分支，控制着糖酵解中间体转化为丝氨酸及其下游物质的通量。磷酸甘油酸脱氢酶（PHGDH）作为丝氨酸合成通路第一步的关键限速酶，控制着丝氨酸的从头合成通路。在多种肿瘤细胞及组织中，PHGDH出现基因扩增，且其异常调控将会影响肿瘤细胞的增殖、凋亡及侵袭等过程。此外，沉默PHGDH基因或者抑制PHGDH酶活力后能够降低具有PHGDH高表达的肿瘤细胞增殖。因此， PHGDH是抗肿瘤研发策略中重要的靶点。本研究采用化合物筛选及结构优化等策略，报道了一类新型PHGDH小分子抑制剂。先导化合物D8显示出良好的酶抑制活性（IC50 = 2.8 ± 0.1μM）、高亲和力（Kd = 2.33 μM），同时对PHGDH基因扩增或高表达的细胞系具有较好的增殖抑制活性。此外，D8能够降低肿瘤细胞MDA-MB-468内的丝氨酸合成。小分子-蛋白共晶复合物结构、分子动力学模拟、氨基酸突变等实验共同揭示了该化合物在靶蛋白NAD+结合口袋的作用模式。重要的是，化合物D8具有优秀的体内药代动力学性质（口服生物利用度为82%）。且能有效抑制人非小细胞肺癌细胞株PC9移植瘤的体内生长。