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

Abstract

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.

Unravelling the Allosteric Targeting of PHGDH at the ACT-Binding Domain with a Photoactivatable Diazirine Probe and Mass Spectrometry Experiments

“…Both molecules thus displayed similar binding epitopes, with a high relative saturation transfer for the aromatic hydrogens ( Figure 5 , blue and red) and a lower relative saturation transfer for the morpholine hydrogens ( Figure 5 , light blue and green) suggesting a similar interaction pattern for 2 and 11 with PHGDH. This interesting pattern also explains, at least in part, why modification/substitution of this aromatic ring has a considerable impact on PHGDH inhibition, as previously reported [ 18 ].…”

“…Early investigations of the structure-activity relationships (SARs) revealed the importance of this para -substitution pattern ( Figure 2 , compare the para -chlorinated derivative 2 and the meta -chlorinated analogue 3 , for instance) [ 14 ]. Moreover, recent studies also demonstrated that structural modifications of the linker and/or the morpholino ring are poorly tolerated and only lead to improved inhibitory potency when coupled with chlorinated para -substitution [ 18 ]. However, at this stage, the precise binding mode of 2 to PHGDH remained mostly unclear.…”

Direct Synthesis of α-Ketothioamide Derivatives through a One-Pot Reaction of Sulfur Ylides, Nitrosobenzenes, and Thioacetic Acid

“…1 H NMR (400 MHz, CDCl 3 ): δ 10.15 (s, 1H), 7.91 (t, J = 9.2 Hz, 4H), 7.85 (m, 1H), 7.62 (m, 1H), 7.42 (t, J = 7.9 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.29 (t, J = 7.5 Hz, 1H), 6.40 (t, J = 3.5 Hz, 1H), 2.44 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ 187. 4,174.5,145.2,137.8,135.7,131.8,130.1,130.0,129.6,129.1,128.2,127.2,122.2,111.3,21.7;HRMS calcd -4-yl)-2-oxo-N-phenylethanethioamide (3s). Purified by column chromatography (silica gel 200−300 mesh, petroleum ether/ethyl acetate = 3:1), yellow solid, yield: 48% (152 mg), mp: 112.9−113.5 °C.…”

Synthesis of α-ketothioamides with elemental sulfur under solvent-free conditions in a mixer mill

“…3 A representative direct application was reported by Frédérick and co-workers, who found inhibitory activities of α-ketothioamide derivatives on phosphoglycerate dehydrogenase (PHGDH) with implications for cancer cell proliferation. 4…”