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

Weinstabl, Harald; Treu, Matthias; Rinnenthal, Joerg; Zahn, Stephan K.; Ettmayer, Peter; Bader, Gerd; Dahmann, Georg; Kessler, Dirk; Rumpel, Klaus; Mischerikow, Nikolai; Savarese, Fabio; Gerstberger, Thomas; Mayer, Moriz; Zoephel, Andreas; Schnitzer, Renate; Sommergruber, Wolfgang; Martinelli, Paola; Arnhof, Heribert; Peric-Simov, Biljana; Hofbauer, Karin S; Garavel, Géraldine; Scherbantin, Yvonne; Mitzner, Sophie; Fett, Thomas N; Scholz, Guido; Bruchhaus, Jens; Burkard, Michelle; Kousek, Roland; Ciftci, Tuncay; Sharps, Bernadette; Schrenk, Andreas; Harrer, Christoph; Haering, Daniela; Wolkerstorfer, B.; Zhang, Xuechun; Lv, Xiaobing; Du, Alicia; Li, Dongyang; Li, Yali; Quant, Jens; Pearson, Mark; McConnell, Darryl B.

doi:10.1021/acs.jmedchem.9b00718

Cited by 54 publications

(45 citation statements)

References 44 publications

(123 reference statements)

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“…Despite this limitation, our model is likely to more accurately model the effects of PHGDH inhibition in select tissues compared to whole body knockout due to the incomplete and transient nature of inhibition of enzymes by small molecules. While there have been many PHGDH inhibitors reported to date [29,30,33,43,44], only NTC-503, PKUMDL-WQ-2101, and PKUMDL-WQ-2201 have been used in vivo, and to our knowledge, their efficacy and long-term toxicity in various tissues have not been characterized. The future comparison between shRNA and pharmacological inhibition will provide important insight into the contribution of PHGDH to normal tissue homeostasis and metabolism.…”

Section: Discussionmentioning

confidence: 99%

PHGDH supports liver ceramide synthesis and sustains lipid homeostasis

et al. 2020

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Background: D-3-phosphoglycerate dehydrogenase (PHGDH), which encodes the first enzyme in serine biosynthesis, is overexpressed in human cancers and has been proposed as a drug target. However, whether PHGDH is critical for the proliferation or homeostasis of tissues following the postnatal period is unknown. Methods: To study PHGDH inhibition in adult animals, we developed a knock-in mouse model harboring a PHGDH shRNA under the control of a doxycycline-inducible promoter. With this model, PHGDH depletion can be globally induced in adult animals, while sparing the brain due to poor doxycycline delivery. Results: We found that PHGDH depletion is well tolerated, and no overt phenotypes were observed in multiple highly proliferative cell compartments. Further, despite detectable knockdown and impaired serine synthesis, liver and pancreatic functions were normal. Interestingly, diminished PHGDH expression reduced liver serine and ceramide levels without increasing the levels of deoxysphingolipids. Further, liver triacylglycerol profiles were altered, with an accumulation of longer chain, polyunsaturated tails upon PHGDH knockdown. Conclusions: These results suggest that dietary serine is adequate to support the function of healthy, adult murine tissues, but PHGDH-derived serine supports liver ceramide synthesis and sustains general lipid homeostasis.

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Section: Discussionmentioning

confidence: 99%

PHGDH supports liver ceramide synthesis and sustains lipid homeostasis

et al. 2020

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“…Weinstabl discovered a cofactor nicotinamide adenine dinucleotide (NADH/NAD + )competitive PHGDH inhibitor, BI-4916, a prodrug of BI-4942. BI-4916 has shown high selectivity against the high cytosolic levels of the competitive cofactors NADH/NAD + with high selectivity via an intracellular ester cleavage mechanism of the ester prodrug to achieve intracellular enrichment of the actual carboxylic acid-based drug (Figure 7) [71].…”

Section: Orthosteric Inhibitorsmentioning

confidence: 99%

The Role of D-3-Phosphoglycerate Dehydrogenase in Cancer

Zhao¹,

Fu²,

Du³

et al. 2020

Int. J. Biol. Sci.

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Serine, a non-essential amino acid, can be imported from the extracellular environment by transporters and de novo synthesized from glycolytic 3-phosphoglycerate (3-PG) in the serine biosynthetic pathway (SSP). It has been reported that active serine synthesis might be needed for the synthesis of proteins, lipids, and nucleotides and the balance of folate metabolism and redox homeostasis, which are necessary for cancer cell proliferation. Human D-3-phosphoglycerate dehydrogenase (PHGDH), the first and only rate-limiting enzyme in the de novo serine biosynthetic pathway, catalyzes the oxidation of 3-PG derived from glycolysis to 3-phosphohydroxypyruvate (3-PHP). PHGDH is highly expressed in tumors as a result of amplification, transcription, or its degradation and stability alteration, which dysregulates the serine biosynthesis pathway via metabolic enzyme activity to nourish tumors. And some recent researches reported that PHGDH promoted some tumors growth via non-metabolic way by upregulating target cancer-promoting genes. In this article, we reviewed the type, structure, expression and inhibitors of PHGDH, as well as the role it plays in cancer and tumor resistance to chemotherapy.

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“…R f 0. 1-Phenyl-2-(piperidin-1-yl)-2-thioxoethan-1-one (15). This compound was synthesized according to General Procedure II using 2-bromo-1-phenylethanone (2.0 g, 10.01 mmol), piperidine (2.99 mL, 30.30 mmol), and sulfur (0.48 g, 15.10 mmol) in DMF (10 mL).…”

Section: General Procedures IImentioning

confidence: 99%

“…Two of them are NAD + -competitive and thus interact with the Rossmann fold (BI-4924 and compound 18). These compounds exhibit PHGDH inhibition in the submicromolar range in isolated enzyme assays but have poor cellular efficacy notably because of the competition with a high intracellular NAD + concentration [14,15]. The other series of inhibitors (CBR-5884, NCT-503, disulfiram, Azacoccone, PKUMLD-WQ-220, Ixocarpolactone) have an allosteric mode of action, and although less effective than the NAD + -competitive compounds, they are usually characterized by a better inhibition profile on cancer cell lines in in vitro and in vivo xenograft models.…”

Section: Introductionmentioning

confidence: 99%

Structure–Activity Relationships (SARs) of α-Ketothioamides as Inhibitors of Phosphoglycerate Dehydrogenase (PHGDH)

et al. 2020

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For many years now, targeting deregulation within cancer cells’ metabolism has appeared as a promising strategy for the development of more specific and efficient cancer treatments. Recently, numerous reports highlighted the crucial role of the serine synthetic pathway, and particularly of the phosphoglycerate dehydrogenase (PHGDH), the first enzyme of the pathway, to sustain cancer progression. Yet, because of very weak potencies usually in cell-based settings, the inhibitors reported so far failed to lay ground on the potential of this approach. In this paper, we report a structure–activity relationship study of a series of α-ketothioamides that we have recently identified. Interestingly, this study led to a deeper understanding of the structure–activity relationship (SAR) in this series and to the identification of new PHGDH inhibitors. The activity of the more potent compounds was confirmed by cellular thermal shift assays and in cell-based experiments. We hope that this research will eventually provide a new entry point, based on this promising chemical scaffold, for the development of therapeutic agents targeting PHGDH.

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

Cited by 54 publications

References 44 publications

PHGDH supports liver ceramide synthesis and sustains lipid homeostasis

PHGDH supports liver ceramide synthesis and sustains lipid homeostasis

The Role of D-3-Phosphoglycerate Dehydrogenase in Cancer

Structure–Activity Relationships (SARs) of α-Ketothioamides as Inhibitors of Phosphoglycerate Dehydrogenase (PHGDH)

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