1. Rational Design of Selective Allosteric Inhibitors of PHGDH and Serine Synthesis with Anti-tumor Activity.
- Author
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Wang Q, Liberti MV, Liu P, Deng X, Liu Y, Locasale JW, and Lai L
- Subjects
- Allosteric Regulation drug effects, Allosteric Site drug effects, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Humans, Models, Molecular, Molecular Structure, Phosphoglycerate Dehydrogenase metabolism, Structure-Activity Relationship, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Drug Design, Enzyme Inhibitors pharmacology, Phosphoglycerate Dehydrogenase antagonists & inhibitors, Serine biosynthesis
- 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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)- Published
- 2017
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