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Application of SIRT1 micro-molecular inhibitor in preparation of medicines for treating or preventing caner and protein deacetylation related diseases

A deacetylation and drug technology is applied in the field of use of SIRT1 small molecule inhibitors in the preparation of drugs for the treatment or prevention of cancer and diseases related to protein deacetylation, and can solve the problems of low inhibition rate, toxic side effects and the like

Inactive Publication Date: 2012-03-14
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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Problems solved by technology

[0006]Because the reported SIRT1 inhibitors have problems such as low inhibition rate and toxic side effects, it is necessary to develop SIRT1 inhibitors with new chemical skeletons in order to adopt chemical synthesis methods Modify the structure of the compound to further improve its biological activity

Method used

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Experimental program
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Embodiment Construction

[0079] 3. Determination of reversibility of DLSI001 inhibitory effect

[0091] In order to study the binding mode of DLSI001 and SIRT1, we used molecular docking technology to dock DLSI001 into the SIRT1 protein structure model established above, and found that DLSI001 was bound to the C pocket of SIRT1 ( Figure 9 A), mainly combined with Phe273, Phe297, Phe309, Phe312, Ile316, Ile347, Phe366, Ile411 by hydrophobic interaction ( Figure 9 B). Therefore, we used the protein site-directed mutagenesis method to mutate the phenylalanine at position 312 of the SIRT1 protein to leucine (F312L), and the isoleucine at position 316 to alanine (I316A). Methods The IC of DLSI001 against wild-type and mutant SIRT1 was determined 50 And the dissociation constant Ki( Figure 10 ), found: 1) IC of mutant I316A and mutant F312L 50 161 μM and 522 μM, respectively, much greater than the IC for wild-type SIRT1 50 ; 2) The Ki of DLSI001 binding to wild-type SIRT1 was 9.61 μM; the Ki of DL...

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Abstract

The invention relates to an application of a compound which has the following chemical structure or its pharmaceutically acceptable salt, solvate, hydrate, prodrug and its pharmaceutical composition in the preparation of medicines for preventing and treating cancer or other protein deacetylation related diseases.

Description

technical field [0001] The present invention relates to a class of novel small molecule inhibitors or pharmaceutically acceptable salts, solvates, hydrates or drugs thereof that can bind to SIRT1 histone deacetylase and inhibit its enzyme activity, thereby inhibiting protein deacetylation Use of the precursor and its pharmaceutical composition in preparing medicines for preventing and treating cancer and other diseases related to protein deacetylation. Background technique [0002] Protein acetylation and deacetylation are two main ways of protein covalent modification, which are catalyzed by histone acetylase and sirtuin respectively. More than 30 years ago, people first discovered histone deacetylases HAD and RPD3 from yeast, and later discovered many histone deacetylases with different functions from different species. According to their correlation with HAD and RPD3, people classify these sirtuin deacetylases as class I and class II histone deacetylases. The recently d...

Claims

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Application Information

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IPC IPC(8): A61K31/343A61K31/5377A61P35/00A61P43/00
Inventor 刘东祥蒋华良
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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