Intracellular Trapping of the Selective Phosphoglycerate Dehydrogenase (PHGDH) Inhibitor BI-4924 Disrupts Serine Biosynthesis
| Autor: | Yvonne Scherbantin, Gerd Bader, thomas Fett, Harald Weinstabl, Sophie Mitzner, Tuncay Ciftci, Bernhard Wolkerstorfer, Jens Bruchhaus, Xiaobing Lv, Dongyang Li, Bernadette Sharps, Daniela Haering, Heribert Arnhof, Nikolai Mischerikow, Geraldine Garavel, Andreas Schrenk, Joerg Rinnenthal, Roland Kousek, Thomas Gerstberger, Guido Scholz, Stephan Karl Zahn, Paola Martinelli, Jens Quant, Renate Schnitzer, Andreas Zoephel, Darryl B. McConnell, Moriz Mayer, Dirk Kessler, Xuechun Zhang, Michelle Burkard, Mark Pearson, Karin S. Hofbauer, Alicia Du, Matthias Treu, Christoph Harrer, Yali Li, Fabio Savarese, Klaus Rumpel, Biljana Peric-Simov, Georg Dahmann, Wolfgang Sommergruber, Peter Ettmayer |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
chemistry.chemical_classification
0303 health sciences biology Dehydrogenase Prodrug Nicotinamide adenine dinucleotide 01 natural sciences Cofactor 0104 chemical sciences Serine 010404 medicinal & biomolecular chemistry 03 medical and health sciences chemistry.chemical_compound chemistry Biochemistry Oxidoreductase Drug Discovery biology.protein Molecular Medicine NAD+ kinase Phosphoglycerate dehydrogenase 030304 developmental biology |
| Zdroj: | Journal of Medicinal Chemistry. 62:7976-7997 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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+. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|