Rational Design of Selective Allosteric Inhibitors of PHGDH and Serine Synthesis with Anti-tumor Activity. Issue 1 (19th January 2017)

• Record Type: Journal Article
• Authors: Wang, Qian; Liberti, Maria V.; Liu, Pei; Deng, Xiaobing; Liu, Ying; Locasale, Jason W.; Lai, Luhua
• Is Part Of: Cell chemical biology. Volume 24:Issue 1(2017)
• Page Start: 55
• Page End: 65
• Publication Date: 2017-01-19
• Subjects: cancer cell metabolism -- PHGDH -- de novo serine synthesis -- allosteric inhibitor -- rational design -- virtual screen -- anti-tumor -- in vivo; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2016.11.013
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical Abstract: Highlights: Two previously unknown allosteric sites on PHGDH were identified Inhibitors that bind to these sites were discovered Inhibitors bound to PHGDH in cells and reduced the synthesis of serine and glycine Inhibitors suppressed tumor growth in mice Abstract : Wang et al. identify allosteric sites on PHGDH and discover inhibitors bound to these sites. These allosteric inhibitors are specific, bind to PHGDH in cells, reduce serine synthesis, and show anti-tumor activity in vivo.