| Literature DB >> 31365252 |
Harald Weinstabl1, Matthias Treu1, Joerg Rinnenthal1, Stephan K Zahn1, Peter Ettmayer1, Gerd Bader1, Georg Dahmann2, Dirk Kessler1, Klaus Rumpel1, Nikolai Mischerikow1, Fabio Savarese1, Thomas Gerstberger1, Moriz Mayer1, Andreas Zoephel1, Renate Schnitzer1, Wolfgang Sommergruber1, Paola Martinelli1, Heribert Arnhof1, Biljana Peric-Simov1, Karin S Hofbauer1, Géraldine Garavel1, Yvonne Scherbantin1, Sophie Mitzner1, Thomas N Fett1, Guido Scholz1, Jens Bruchhaus1, Michelle Burkard1, Roland Kousek1, Tuncay Ciftci2, Bernadette Sharps1, Andreas Schrenk1, Christoph Harrer1, Daniela Haering1, Bernhard Wolkerstorfer1, Xuechun Zhang3, Xiaobing Lv3, Alicia Du3, Dongyang Li3, Yali Li3, Jens Quant1, Mark Pearson1, Darryl B McConnell1.
Abstract
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+.Entities:
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Year: 2019 PMID： 31365252 DOI： 10.1021/acs.jmedchem.9b00718
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446