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Intracellular Trapping of the Selective Phosphoglycerate Dehydrogenase (PHGDH) Inhibitor BI-4924 Disrupts Serine Biosynthesis

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posted on 14.08.2019, 18:37 by Harald Weinstabl, Matthias Treu, Joerg Rinnenthal, Stephan K. Zahn, Peter Ettmayer, Gerd Bader, Georg Dahmann, Dirk Kessler, Klaus Rumpel, Nikolai Mischerikow, Fabio Savarese, Thomas Gerstberger, Moriz Mayer, Andreas Zoephel, Renate Schnitzer, Wolfgang Sommergruber, Paola Martinelli, Heribert Arnhof, Biljana Peric-Simov, Karin S. Hofbauer, Géraldine Garavel, Yvonne Scherbantin, Sophie Mitzner, Thomas N. Fett, Guido Scholz, Jens Bruchhaus, Michelle Burkard, Roland Kousek, Tuncay Ciftci, Bernadette Sharps, Andreas Schrenk, Christoph Harrer, Daniela Haering, Bernhard Wolkerstorfer, Xuechun Zhang, Xiaobing Lv, Alicia Du, Dongyang Li, Yali Li, Jens Quant, Mark Pearson, Darryl B. McConnell
Phosphoglycerate dehydrogenase (PHGDH) is known to be the rate-limiting enzyme in the serine synthesis pathway in humans. It converts glycolysis-derived 3-phosphoglycerate to 3-phosphopyruvate in a co-factor-dependent oxidation reaction. Herein, we report the discovery of BI-4916, a prodrug of the co-factor nicotinamide adenine dinucleotide (NADH/NAD+)-competitive PHGDH inhibitor BI-4924, which has shown high selectivity against the majority of other dehydrogenase targets. Starting with a fragment-based screening, a subsequent hit optimization using structure-based drug design was conducted to deliver a single-digit nanomolar lead series and to improve potency by 6 orders of magnitude. To this end, an intracellular ester cleavage mechanism of the ester prodrug was utilized to achieve intracellular enrichment of the actual carboxylic acid based drug and thus overcome high cytosolic levels of the competitive cofactors NADH/NAD+.