title: Rational Design of Selective Allosteric Inhibitors of PHGDH and Serine Synthesis with Anti-tumor Activity.
abstract: Metabolic reprogramming in cancer cells facilitates growth and proliferation. Increased activity of the serine biosynthetic pathway through the enzyme phosphoglycerate dehydrogenase (PHGDH) contributes to tumorigenesis. With a small substrate and a weak binding cofactor, (NAD+), inhibitor development for PHGDH remains challenging. Instead of targeting the PHGDH active site, we computationally identified two potential allosteric sites and virtually screened compounds that can bind to these sites. With subsequent characterization, we successfully identified PHGDH non-NAD+-competing allosteric inhibitors that attenuate its enzyme activity, selectively inhibit de novo serine synthesis in cancer cells, and reduce tumor growth in vivo. Our study not only identifies novel allosteric inhibitors for PHGDH to probe its function and potential as a therapeutic target, but also provides a general strategy for the rational design of small-molecule modulators of metabolic enzyme function.
authors.affiliation: BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke Cancer Institute, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Molecular Biology and Genetics, Graduate Field of Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Maria V
authors.initials: MV
authors.lastname: Liberti
authors.affiliation: BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Liu
authors.affiliation: Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Deng
authors.affiliation: BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China; Center for Quantitative Biology, Peking University, Beijing 100871, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke Cancer Institute, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: jason.locasale@duke.edu.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Locasale
authors.affiliation: BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Center for Quantitative Biology, Peking University, Beijing 100871, China. Electronic address: lhlai@pku.edu.cn.
authors.forename: Luhua
authors.initials: L
authors.lastname: Lai
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000495:Allosteric Site / Q000187:drug effects; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D050543:Phosphoglycerate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012694:Serine / Q000096:biosynthesis*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D012694:Serine; D050543:Phosphoglycerate Dehydrogenase
keywords: PHGDH; allosteric inhibitor; anti-tumor; cancer cell metabolism; de novo serine synthesis; in vivo; rational design; virtual screen