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

Journal of Medicinal Chemistry
Harald WeinstablDarryl B McConnell

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+.

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Citations

Jul 1, 2020·Cellular and Molecular Life Sciences : CMLS·Giulia MurtasLoredano Pollegioni
Jun 19, 2020·Cancer & Metabolism·Yun Pyo KangGina M DeNicola
Jan 30, 2021·Nature Metabolism·Shauni L GeeraertsKim R Kampen
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May 21, 2020·Journal of Medicinal Chemistry·Matthew D Lloyd
Mar 19, 2021·Cellular Oncology (Dordrecht)·Mingxue LiHua Li
Mar 25, 2021·Nature Metabolism·Kevin EadeRando Allikmets
Mar 24, 2021·The Journal of Biological Chemistry·Hanyu XuLuhua Lai
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Jan 14, 2021·Cancer Discovery·Stefan BjelosevicRicky W Johnstone
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Nov 24, 2020·Journal of Medicinal Chemistry·Wolfgang JahnkeTatsuya Urushima
Dec 5, 2021·Nature Reviews. Drug Discovery·Zachary E StineChi V Dang

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