Discovery of Novel Drug-like PHGDH Inhibitors to Disrupt Serine Biosynthesis for Cancer Therapy
Discovery of Novel Drug-like PHGDH Inhibitors to Disrupt Serine Biosynthesis for Cancer Therapy
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发现新型药物样 PHGDH 抑制剂，可破坏丝氨酸生物合成，用于癌症治疗
DOI：
10.1021/acs.jmedchem.2c01202
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发表时间：
2023
影响因子：
7.3
通讯作者：
Ping Tian
中科院分区：
文献类型：
--
作者：
Dingding Gao;Shuai Tang;Yixin Cen;Liang Yuan;Xiaojing Lan;Qing-Hua Li;Guo-Qiang Lin;Min Huang;Ping Tian
磷酸甘油酸脱氢酶（phosphoglycerate dehydrogenase， PHGDH）是丝氨酸生物合成途径中的限速酶，在许多恶性肿瘤细胞中异常过表达，是癌症治疗的一个有希望的靶点。在这里，我们报道了一系列使用集中化合物筛选和结构优化方法的新型PHGDH抑制剂。该先导化合物dd8具有良好的酶抑制活性（IC50= 2.8±0.1 μM）、高的结合亲和力（Kd= 2.33 μM）和对phgdh基因扩增或过表达的细胞株的敏感性。此外，d8被证明可以限制MDA-MB-468细胞中葡萄糖的新丝氨酸合成。通过x射线晶体学分析、分子动力学模拟和诱变实验，发现PHGDH的结合位点位于NAD+结合口袋内的D175。最后，d8在PC9异种移植小鼠模型中表现出优异的体内药代动力学特性（F= 82.0%），具有明显的抗肿瘤作用。
Being the rate-limiting enzyme within the serine biosynthesis pathway, phosphoglycerate dehydrogenase (PHGDH) is abnormally overexpressed in numerous malignant tumor cells and is a promising target for cancer treatment. Here, we report a series of novel PHGDH inhibitors using a focused compound screening and structural optimization approach. The lead compoundD8displayed good enzymatic inhibitory activity (IC50= 2.8 ± 0.1 μM), high binding affinity (Kd= 2.33 μM), and sensitivity to the cell lines with thePHGDHgene amplification or overexpression. Furthermore,D8was proven to restrict thede novoserine synthesis from glucose within MDA-MB-468 cells. X-ray crystallographic analysis, molecular dynamics simulations, and mutagenesis experiments on PHGDH revealed the binding site at D175 inside the NAD+-binding pocket. Finally,D8exhibited excellentin vivopharmacokinetic properties (F= 82.0%) and exerted evident antitumor efficacy in the PC9 xenograft mouse model.