Given the putative role of PHGDH in cancer, development of inhibitors is
required to explore its function. In this context, we established and validated
a straightforward enzymatic assay suitable for high-throughput screening and we
identified inhibitors with similar chemical scaffolds. Through a convergent
pharmacophore approach, we synthesized α-ketothioamides
that exhibit interesting in vitro PHGDH inhibition and encouraging cellular
results. These novel probes may be used to understand the emerging biology of
this metabolic target.
Recent advances in the understanding of the relationship between cancer and metabolism have highlighted the relevance of the serine synthetic pathway (SSP), which consists of three successive enzymatic reactions. Enzymes of the SSP, such as phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT-1), were recently highlighted because they are amplified in a significant subset of human tumors, and their suppression by RNAi caused a decrease in cancer cell survival and growth. Currently, the discovery of drugs that inhibit these enzymes is still in its infancy, and the identification of suitable inhibitors could serve to understand the emerging biology of these metabolic enzymes. In this review, we present the SSP as a significant and novel emerging area for medicinal chemistry and we provide an overview of one of the key enzymes of the pathway, PHGDH.
Due to rising costs and the difficulty to identify new targets, drug repurposing appears as a viable strategy for the development of new anti-cancer treatments. Although the interest of disulfiram (DSF), an anti-alcohol drug, to treat cancer was reported for many years, it is only very recently that one anticancer mechanism-of-action was highlighted. This would involve the inhibition of the p97 segregase adaptor NPL4, which is essential for the turnover of proteins involved in multiple regulatory and stress-response intracellular pathways. However, recently DSF was also reported as one of the first phosphoglycerate dehydrogenase (PHGDH) inhibitors, a tetrameric enzyme catalyzing the initial step of the serine synthetic pathway that is highly expressed in numerous cancer types. Here, we investigated the structure-activity relationships (SAR) of PHGDH inhibition by disulfiram analogues as well as the mechanism of action of DSF on PHGDH via enzymatic and cell-based evaluation, mass spectrometric and mutagenesis experiments.
Lactate dehydrogenases
(LDHs) are tetrameric enzymes of major significance
in cancer metabolism as well as promising targets for cancer therapy.
However, their wide and polar catalytic sites make them a challenging
target for orthosteric inhibition. In this work, we conceived to target
LDH tetramerization sites with the ambition of disrupting their oligomeric
state. To do so, we designed a protein model of a dimeric LDH-H. We
exploited this model through WaterLOGSY nuclear magnetic resonance
and microscale thermophoresis for the identification and characterization
of a set of α-helical peptides and stapled derivatives that
specifically targeted the LDH tetramerization sites. This strategy
resulted in the design of a macrocyclic peptide that competes with
the LDH tetramerization domain, thus disrupting and destabilizing
LDH tetramers. These peptides and macrocycles, along with the dimeric
model of LDH-H, constitute promising pharmacological tools for the de novo design and identification of LDH tetramerization
disruptors. Overall, our study demonstrates that disrupting LDH oligomerization
state by targeting their tetramerization sites is achievable and paves
the way toward LDH inhibition through this novel molecular mechanism.
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