Identification of substituted 3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase

Dragovich, Peter S.; Fauber, Benjamin P.; Boggs, Jason; Chen, J; Corson, Laura; Ding, Charles Z.; Ge, Hongxiu; Giannetti, Anthony M.; Hunsaker, Thomas; Labadie, Sharada S.; Li, C; Liu, Y; Ma, Shuguang; Malek, Shiva; Peterson, David; Pitts, Keith; Purkey, Hans E.; Robarge, Kirk; Salphati, Laurent; Sideris, Steve; Ultsch, Mark; VanderPorten, Erica C.; Wang, J; Wei, BinQing; Xu, Qing; Yen, Ivana; Qin, Ya‐Zhen; Zhang, H; Zhang, X; Zhou, Aihe

doi:10.1016/j.bmcl.2014.06.076

Cited by 38 publications

(47 citation statements)

References 39 publications

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“…However, in cancer cells, irrespective of oxygen availability, glycolysis followed by production of lactate through LDH is the preferred pathway, enhancing the production of metabolic precursors required for biosynthesis of cellular macromolecules. The recognition in a growing number of cancers of the central role of both LDH A and B isoforms (Fiume et al, 2014; McCleland et al, 2013; Rodriguez et al, 2003) has driven the identification of small-molecule inhibitors, including mercaptocyclohex-2-enone derivatives that bind away from the NAD-binding pocket and are not competitive inhibitors (Dragovich et al, 2014), as well as sulfamoylquinoline benzoic acid derivatives, which compete with NAD binding to LDH (Billiard et al, 2013). To evaluate the potential of cryo-EM to determine structures of a small protein complex such as LDH and localize the binding sites of potential small-molecule inhibitors, we carried out cryo-EM analysis of LDH B in complex with GSK2837808A, a 650 Dalton compound in the quinoline 3-sulfonamide series (Billiard et al, 2013).…”

Section: Resultsmentioning

confidence: 99%

Breaking Cryo-EM Resolution Barriers to Facilitate Drug Discovery

Merk

Bartesaghi

Banerjee

et al. 2016

Cell

489

430

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SUMMARY Recent advances in single-particle cryoelecton microscopy (cryo-EM) are enabling generation of numerous near-atomic-resolution structures for well-ordered protein complexes with sizes ≥ ~200 kDa. Whether cryo-EM methods are equally useful for high-resolution structural analysis of smaller, dynamic protein complexes such as those involved in cellular metabolism remains an important question. Here, we present 3.8 Å resolution cryo-EM structures of isocitrate dehydrogenase (93 kDa) and identify the nature of conformational changes induced by binding of the allosteric small-molecule inhibitor ML309. We also report 2.8-Å- and 1.8-Å-resolution structures of the cancer targets lactate dehydrogenase (145 kDa) and glutamate dehydrogenase (334 kDa), respectively. With these results, two perceived barriers in single-particle cryo-EM are overcome: our tests demonstrated crossing 2 Å resolution and obtaining maps of proteins with sizes < 100 kDa, demonstrating that cryo-EM can be used to investigate a broad spectrum of drug-target interactions and dynamic conformational states.

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Section: Resultsmentioning

confidence: 99%

Breaking Cryo-EM Resolution Barriers to Facilitate Drug Discovery

Merk

Bartesaghi

Banerjee

et al. 2016

Cell

489

430

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“…Nitro aromatic 11 (36v‐803) is found in protein complex 4qo7, a ( Homo sapiens ) lactate dehydrogenase A . As is detailed in Figure S15 (Supporting Information), the carboxylate of Asp‐165 is located directly above the nitro group (N⋅⋅⋅O=3.38 Å in chain A).…”

Section: Resultsmentioning

confidence: 99%

“…As is detailed in Figure S15 (Supporting Information), the carboxylate of Asp‐165 is located directly above the nitro group (N⋅⋅⋅O=3.38 Å in chain A). In a study testing 60 ligands as inhibitors, 11 was found to be 31 times more potent than the ‐Br analogue (LC 50 =1.7 vs. 53 μ m ) …”

Section: Resultsmentioning

confidence: 99%

π‐Hole Interactions Involving Nitro Aromatic Ligands in Protein Structures

Bauzá

Mooibroek

2019

Chemistry A European J

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Studying noncanonical intermolecular interactions between a ligand and a protein constitutes an emerging research field. Identifying synthetically accessible molecular fragments that can engage in intermolecular interactions is a key objective in this area. Here, it is shown that so‐called “π‐hole interactions” are present between the nitro moiety in nitro aromatic ligands and lone pairs within protein structures (water and protein carbonyls and sulfurs). Ample structural evidence was found in a PDB analysis and computations reveal interaction energies of about −5 kcal mol−1 for ligand–protein π‐hole interactions. Several examples are highlighted for which a π‐hole interaction is implicated in the superior binding affinity or inhibition of a nitro aromatic ligand versus a similar non‐nitro analogue. The discovery that π‐hole interactions with nitro aromatics are significant within protein structures parallels the finding that halogen bonds are biologically relevant. This has implications for the interpretation of ligand–protein complexation phenomena, for example, involving the more than 50 approved drugs that contain a nitro aromatic moiety.

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“…In addition, the high-throughput screening (HTS) of the Roche and Genentech chemical archives, using a fluorescence-based assay which monitored the disappearance of the NADH co-factor during enzymatic conversion of pyruvate to lactate, allowed to identify novel class of 3-hydroxy-2-mercaptocyclohex-2-enone-containing inhibitors of human LDH-5 effectively interacting with its active site, due to imitate the pyruvate substrate, and exhibiting good pharmacokinetic properties after oral administration to rats. However, it was impossible to show the ability of these compounds to limit the lactate production in the epithelial cell line of breast cancer in vitro study [89].…”

Section: Synthetic Ldh-5 Inhibitors and Their Therapeutic Potentialmentioning

confidence: 99%