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Benzoyl hydrazine allosteric inhibitor for D-3-phosphoglycerate dehydrogenase and applications of benzoyl hydrazine allosteric inhibitor

A technique of use and medicinal salt, applied in the field of allosteric inhibitors of benzohydrazide D-3-phosphoglycerate dehydrogenase and its use, can solve the problems of no drug effect, no PHGDH inhibitor, etc.

Inactive 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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  • Benzoyl hydrazine allosteric inhibitor for D-3-phosphoglycerate dehydrogenase and applications of benzoyl hydrazine allosteric inhibitor
  • Benzoyl hydrazine allosteric inhibitor for D-3-phosphoglycerate dehydrogenase and applications of benzoyl hydrazine allosteric inhibitor
  • Benzoyl hydrazine allosteric inhibitor for D-3-phosphoglycerate dehydrogenase and applications of benzoyl hydrazine allosteric inhibitor

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1, the discovery of PHGDH allosteric inhibitor

[0037] 1. Prediction of PHGDH allosteric sites

[0038] 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

[0041] Embodiment 2, the synthesis of allosteric molecule

[0042] 1. Design of PKUMDL-WL-2101 analogs

[0043] According to the docking model of the active compound compound (E)-2,4-dihydroxy-N'-(2-hydroxy-5-nitrobenzylidene)benzohydrazide (PKUMDL-WL-2101) bound to PHGDH ( See figure 2 ), the interaction mode between the small molecule and PHDGH can be seen: two benzene rings occupy the hydrophobic cavity in the pocket, and on the benzene ring of the acyl group, the hydroxyl group substituted at position 4 can form a hydrogen bond with phenylalanine at position 261; The substituted hydroxyl can form a hydrogen bond with 264 glutamic acid; the carbonyl oxygen in the hydrazide chain can form a hydrogen bond with 57 lysine, and the hydrazide nitrogen can form a hydrogen bond with 264 glutamic acid; on another benzene ring, The nitro group at position 3 can form hydrogen bonds with arginine at position 134 or alanine at position 55; the ring also has electrostatic interactions...

Embodiment 3

[0094] Example 3, Fluorescence Kinetic Method Determination of PHGDH Enzyme Activity in Vitro of PKUMDL-WL-2101 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 benzoyl hydrazine allosteric inhibitor for D-3-phosphoglycerate dehydrogenase and applications of the benzoyl hydrazine allosteric inhibitor, wherein the structure of the benzoyl hydrazine allosteric inhibitor is shown as the formula I, R1, R2, R3, R4, R5, R6 and R7 are the same or different, and respectively represent hydrogen, halogen, nitryl, hydroxyl, amino or substituted amino, alkyl, alkoxy, and benzyloxy or halogen substituted alkyl independently, or the adjacent substituent groups can form a ring. The in-vitro enzymatic activity testing, cell viability testing and mouse heterotransplantation model experiment prove that the compound can specifically inhibit the activity of D-3-phosphoglycerate dehydrogenase, and the growth of cancer cells is delayed by reducing the overexpression of D-3-phosphoglycerate dehydrogenase in the cancer cells. The compound can be used for treating, preventing or inhibiting the tumor diseases including breast cancer, colon cancer, melanoma and non-small cell lung cancer when used independently or in combination with other anti-cancer drugs. The formula I is shown in the description.

Description

technical field [0001] The invention relates to medicines for treating and preventing various diseases caused by serine metabolic disorders, in particular to N'-substituted benzohydrazide compounds as D-3-phosphoglycerate dehydrogenase inhibitors, the compound and its Application of combination medicine in the treatment of breast cancer, 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, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/166A61K31/341A61P35/00
CPCA61K31/166A61K31/341A61K2300/00
Inventor 来鲁华刘莹王倩刘培
Owner PEKING UNIV
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