Phosphoglycerate dehydrogenase (PHGDH) is an essential enzyme catalyzing the synthesis of amino acid serine. PHGDH is important for maintaining the poorly differentiated, stem-like state of cancer stem-like cells (CSLCs). Typically, high levels of PHGDH associate with enhanced proliferation and poor prognosis in various types of cancers. As a result, the cancer cells that harbor high levels of PHGDH are more susceptible to PHGDH inhibition.

PHGDH plays an important role in the maintenance of self-renewal and poorly differentiated state of the CSLCs through modulation of autophagy. Moreover, knockdown of PHGDH significantly attenuates the tumor growth and prolongs the survival of tumor bearing mice. The pancreatic adenocarcinoma patients with low PHGDH expression have better overall survival. Mechanistically, knockdown of PHGDH inhibits cell proliferation and tumorigenesis through disrupting the cell-cell tight junctions and the related proteins expression. Besides catalyzing serine synthesis to activate AKT pathway, PHGDH interacts with the translation initiation factors eIF4A1 and eIF4E and facilitates the assembly of the complex eIF4F on 5’ mRNA structure to promote the relevant proteins expression.

BI-4924 is a highly potent co-factor nicotinamide adenine dinucleotide (NADH/NAD+)-competitive PHGDH inhibitor. In particular, BI-4924 is a lipophilic, highly plasma protein bound selective phosphoglycerate dehydrogenase (PHGDH) inhibitor (IC50=3 nM) with excellent microsomal, as well as hepatocytic stability. Besides, intracellular trapping of BI-4924 disrupts serine biosynthesis with an IC50 of 2200 nM at 72 h. Ultimately, BI-4924 shows high selectivity against the majority of other dehydrogenase targets.

All in all, PHGDH promotes pancreatic cancer development through enhancing the translation initiations by interacting with eIF4A1 and eIF4E. Inhibiting the interactions of PHGDH/eIF4A1 and PHGDH/eIF4E will provide potential targets for anti-tumor therapeutics development.

Weinstabl H, et al. Intracellular Trapping of the Selective Phosphoglycerate Dehydrogenase (PHGDH) Inhibitor BI-4924 Disrupts Serine Biosynthesis. J Med Chem. 2019 Aug 14.