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Furan D-3-phosophoglycerate dehydrogenase allosteric inhibitor and application thereof

A kind of use, the technology of medicinal salt, applied in the direction of medical preparations containing active ingredients, pharmaceutical formulas, organic chemistry, etc., can solve the problems of no drug effect, no PHGDH inhibitor, etc.

Active Publication Date: 2017-04-19
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

So far, there have been no reports of PHGDH inhibitors entering clinical research, nor have their drug effects reported in combination with anticancer drugs

Method used

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  • Furan D-3-phosophoglycerate dehydrogenase allosteric inhibitor and application thereof
  • Furan D-3-phosophoglycerate dehydrogenase allosteric inhibitor and application thereof
  • Furan D-3-phosophoglycerate dehydrogenase allosteric inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1, the discovery of PHGDH allosteric inhibitor

[0038] 1. Prediction of PHGDH allosteric sites

[0039] The allosteric sites of PHGDH (PDB code: 2G76) were predicted using the protein surface exploration program CAVITY. First, the program probes the surface of the protein by erasing the ball method to find potential binding sites on the protein surface; then, the program uses the empirical formula (CavityScore=(Volume-AdjustVolume) / (SurfaceArea-AdjustSurfaceArea)) to analyze the protein-binding small molecule ability to score. AdjustVolume and AdjustSurfaceArea are related to the hydrophobic area of ​​residues and the number of hydrogen bond acceptors and donors in the predicted sites. by the maximum pK for known binding site-ligand binding pairs D Score and compare with known experimental pK D A good linear correlation was obtained by fitting the values. Therefore, the program can score the predicted binding site-ligand maximum pK according to the abov...

Embodiment 2

[0042] Embodiment 2, the synthesis of allosteric molecule

[0043] 1. Design of PKUMDL-WL-2201 analogs

[0044] From the active compound (E)-2-chloro-4-(5-((2-(ethylcarbamoyl)hydrazono)methyl)furan-2-yl)benzoic acid (named PKUMDL-WL-2201 ) docking model with PHGDH ( figure 2 ), the interaction mode between small molecules and PHGDH can be seen: the 2-phenylfuran aromatic ring occupies the hydrophobic cavity in the pocket, and the 4-position carboxyl oxygen in the benzene ring can interact with 11-position serine, 35-position leucine or 34-position asparagus Amides form hydrogen bonds; thiosemicarbazide groups may interact with other electronegative groups in PHGDH. We design a series of compounds through strategies such as molecular isosterism.

[0045] 2. Synthesis of PKUMDL-WL-2201 and its analogs

[0046] Taking (E)-2-chloro-4-(5-((2-(ethylcarbamoyl)hydrazono)methyl)furan-2-yl)benzoic acid (PKUMDLWL-2201) as an example to describe furan Synthesis of PHGDH-like inhibit...

Embodiment 3

[0094] Example 3, Fluorescence Kinetic Method Determination of PHGDH Enzyme Activity in Vitro of PKUMDL-WL-2201 and Its Analogs

[0095] The determination of PHGDH enzyme activity is realized by detecting the fluorescence emission spectrum of NADH at 456nm. First, PHGDH (final concentration 30 ng / μL) was incubated with HEPES buffer (25 mM, pH 7.1, 400 mM KCl), 5 μM PLP, 0.5 mM αKG, 150 μM NADH and PSAT1 (final concentration 30 ng / μL) in a 96-well plate for 10 minutes. Subsequently, 10 μL of DMSO (control group) or DMSO solution containing small molecules was added, and shaken and balanced at 25° C. at 550 rpm for 5 minutes. The final concentration (v / v) of DMSO was kept at 5% in the enzyme activity test system. Finally, Pser aqueous solution (final concentration 0.5mM) was added to start the reaction, and the consumption of NADH at 456nm was monitored over time with a UV-Vis microplate reader. Protein activity was assessed using the initial reaction rate within 30 s, where N...

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Abstract

The invention discloses a furan D-3-phosophoglycerate dehydrogenase allosteric inhibitor and an application thereof. The structure of the furan D-3-phosophoglycerate dehydrogenase allosteric inhibitor is shown in a formula I defined in the specification, wherein R1, R2 and R3 are same or different, and each of R1, R2 and R3 independently represents hydrogen, halogen, nitryl, hydroxyl, amino, carboxyl, alkyl, alkoxy, halogen substituted alkyl, carboxylic acid ester, sulphonylamino, acylamino or N-alkyl substituted acylamino, or two adjacent substituent groups are cyclized; R4 represents alkyl, halogen substituted alkyl, amino, cycloalkyl, aryl or substituted aryl; and X is O, N or S. Through an in-vitro enzyme activity test, a cell activity test and a mouse xenograft transplantation model experiment, it is proved that a compound can specifically inhibit the activity of a D-3-phosophoglycerate dehydrogenase, and cancer cell growth is delayed by reducing over-expression of the D-3-phosophoglycerate dehydrogenase in cancer cells. The compound is applied separately or is combined with other anti-cancer drugs to be applied, and can treat, prevent or inhibit tumor diseases such as breast cancers, colon cancers, melanin tumors, non-small cell lung cancers and the like.

Description

technical field [0001] The invention relates to medicines for treating and preventing various diseases caused by serine metabolic disorders, in particular to furan compounds as D-3-phosphoglycerate dehydrogenase inhibitors, and the compound and its combination medicine are effective in treating breast cancer, Applications in colon cancer, melanoma, non-small cell lung cancer, and other diseases. Background technique [0002] D-3-phosphoglycerate dehydrogenase (PHGDH) in the human body catalyzes the first step of serine synthesis and is a key enzyme in the serine synthesis pathway. PHGDH was confirmed to be overexpressed in 40% of human melanoma cells or 70% of triple-negative breast cancer cells in 2011. The knockout experiment of PHGDH gene found that the growth of these cancer cells in vivo and in vitro was greatly reduced. Amplitude suppression [(1) Locasale, J.W., Grassian, A.R., Melman, T., Lyssiotis, C.A., Mattaini, K.R., Bass, A.J., Heffron, G., Metallo, C.M., Murane...

Claims

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Application Information

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IPC IPC(8): A61K31/341A61P35/00C07D307/52
CPCA61K31/341C07D307/52
Inventor 来鲁华刘莹王倩刘培
Owner PEKING UNIV
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