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Rational Design of Selective Allosteric Inhibitors of PHGDH and Serine Synthesis with Anti-tumor Activity.

Publication ,  Journal Article
Wang, Q; Liberti, MV; Liu, P; Deng, X; Liu, Y; Locasale, JW; Lai, L
Published in: Cell Chem Biol
January 19, 2017

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.

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Published In

Cell Chem Biol

DOI

EISSN

2451-9448

Publication Date

January 19, 2017

Volume

24

Issue

1

Start / End Page

55 / 65

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Structure-Activity Relationship
  • Serine
  • Phosphoglycerate Dehydrogenase
  • Molecular Structure
  • Models, Molecular
  • Humans
  • Enzyme Inhibitors
  • Drug Screening Assays, Antitumor
  • Drug Design
 

Citation

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Wang, Q., Liberti, M. V., Liu, P., Deng, X., Liu, Y., Locasale, J. W., & Lai, L. (2017). Rational Design of Selective Allosteric Inhibitors of PHGDH and Serine Synthesis with Anti-tumor Activity. Cell Chem Biol, 24(1), 55–65. https://doi.org/10.1016/j.chembiol.2016.11.013
Wang, Qian, Maria V. Liberti, Pei Liu, Xiaobing Deng, Ying Liu, Jason W. Locasale, and Luhua Lai. “Rational Design of Selective Allosteric Inhibitors of PHGDH and Serine Synthesis with Anti-tumor Activity.Cell Chem Biol 24, no. 1 (January 19, 2017): 55–65. https://doi.org/10.1016/j.chembiol.2016.11.013.
Wang Q, Liberti MV, Liu P, Deng X, Liu Y, Locasale JW, et al. Rational Design of Selective Allosteric Inhibitors of PHGDH and Serine Synthesis with Anti-tumor Activity. Cell Chem Biol. 2017 Jan 19;24(1):55–65.
Wang, Qian, et al. “Rational Design of Selective Allosteric Inhibitors of PHGDH and Serine Synthesis with Anti-tumor Activity.Cell Chem Biol, vol. 24, no. 1, Jan. 2017, pp. 55–65. Pubmed, doi:10.1016/j.chembiol.2016.11.013.
Wang Q, Liberti MV, Liu P, Deng X, Liu Y, Locasale JW, Lai L. Rational Design of Selective Allosteric Inhibitors of PHGDH and Serine Synthesis with Anti-tumor Activity. Cell Chem Biol. 2017 Jan 19;24(1):55–65.

Published In

Cell Chem Biol

DOI

EISSN

2451-9448

Publication Date

January 19, 2017

Volume

24

Issue

1

Start / End Page

55 / 65

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Structure-Activity Relationship
  • Serine
  • Phosphoglycerate Dehydrogenase
  • Molecular Structure
  • Models, Molecular
  • Humans
  • Enzyme Inhibitors
  • Drug Screening Assays, Antitumor
  • Drug Design