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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Wang, Q; Liberti, MV; Liu, P; Deng, X; Liu, Y; Locasale, JW; Lai, L

Published Date

  • January 19, 2017

Published In

Volume / Issue

  • 24 / 1

Start / End Page

  • 55 - 65

PubMed ID

  • 28042046

Pubmed Central ID

  • PMC5915676

Electronic International Standard Serial Number (EISSN)

  • 2451-9448

Digital Object Identifier (DOI)

  • 10.1016/j.chembiol.2016.11.013


  • eng

Conference Location

  • United States