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Discovery of Novel Drug-like PHGDH Inhibitors to Disrupt Serine Biosynthesis for Cancer Therapy

文献类型：期刊论文

作者Gao, Dingding1; Tang, Shuai2,3; Cen, Yixin1; Yuan, Liang3; Lan, Xiaojing3; Li, Qing-Hua1; Lin, Guo-Qiang1; Huang, Min3; Tian, Ping1
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-01-03
页码21
ISSN号0022-2623
DOI10.1021/acs.jmedchem.2c01202
通讯作者Gao, Dingding(gaodingding@shutcm.edu.cn) ; Li, Qing-Hua(qinghuali@shutcm.edu.cn) ; Huang, Min(mhuang@simm.ac.an) ; Tian, Ping(tianping@shutcm.edu.cn)
英文摘要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 compound D8 displayed good enzymatic inhibitory activity (IC50 = 2.8 +/- 0.1 mu M), high binding affinity (Kd = 2.33 mu M), and sensitivity to the cell lines with the PHGDH gene amplification or overexpression. Furthermore, D8 was proven to restrict the de novo serine 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, D8 exhibited excellent in vivo pharmacokinetic properties (F = 82.0%) and exerted evident antitumor efficacy in the PC9 xenograft mouse model.
WOS关键词MOLECULAR-DYNAMICS ; DEHYDROGENASE ; METABOLISM ; IDENTIFICATION ; PATHWAY ; GLYCINE ; CELLS ; MODEL
资助项目National Key R&D Program of China[2022YFF1202600] ; National Natural Science Foundation of China[81903423] ; National Natural Science Foundation of China[91957126] ; Shanghai Sailing Program[19YF1449300] ; Program of Shanghai Academic/Technology Research Leader[20XD1403600] ; Program of Shanghai Academic/Technology Research Leader[20XD1424800] ; Shanghai Municipal Education Commission[2019-01-07-00-10-E00072] ; Science and Technology Commission of Shanghai Municipality[20400750300] ; Shanghai Municipal Health Commission/Shanghai Municipal Administration of Traditional Chinese Medicine[ZY (2021 - 2023) -0501] ; Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine[ZYYCXTD-D-202004]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000908887700001
源URL[http://119.78.100.183/handle/2S10ELR8/303890]  
专题新药研究国家重点实验室
通讯作者Gao, Dingding; Li, Qing-Hua; Huang, Min; Tian, Ping
作者单位1.Shanghai Univ Tradit Chinese Med, Innovat Res Inst Tradit Chinese Med, Res Ctr Chiral Drugs, Shanghai Frontiers Sci Ctr TCM Chem Biol, Shanghai 201203, Peoples R China
2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Gao, Dingding,Tang, Shuai,Cen, Yixin,et al. Discovery of Novel Drug-like PHGDH Inhibitors to Disrupt Serine Biosynthesis for Cancer Therapy[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023:21.
APA Gao, Dingding.,Tang, Shuai.,Cen, Yixin.,Yuan, Liang.,Lan, Xiaojing.,...&Tian, Ping.(2023).Discovery of Novel Drug-like PHGDH Inhibitors to Disrupt Serine Biosynthesis for Cancer Therapy.JOURNAL OF MEDICINAL CHEMISTRY,21.
MLA Gao, Dingding,et al."Discovery of Novel Drug-like PHGDH Inhibitors to Disrupt Serine Biosynthesis for Cancer Therapy".JOURNAL OF MEDICINAL CHEMISTRY (2023):21.

入库方式： OAI收割

来源：上海药物研究所

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