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CN-117357507-B - Application of small molecular compound YZL-51N in preparation of SIRT7 selective inhibitor

CN117357507BCN 117357507 BCN117357507 BCN 117357507BCN-117357507-B

Abstract

The invention provides an application of a small molecular compound YZL-51N in preparing SIRT7 selective inhibitor. The invention discovers that a small molecular compound YZL-51N can be used as a specific small molecular inhibitor of SIRT 7. The invention utilizes the polypeptide deacetylation to verify that the compound YZL-51N can effectively inhibit the activity of SIRT7 deacetylase. Compared with other sirtuins family members, the invention also proves that YZL-51N has stronger interaction affinity with SIRT7 through a BLI experiment method. The invention confirms that the small molecular compound is inserted into the pocket and interacted with the hot spot amino acid through a molecular docking experiment. In the cell model, YZL-51N can also specifically inhibit SIRT7 and supplement its substrate. The compound can effectively inhibit SIRT7-ATM cell signal path under the stimulation of ion radiation.

Inventors

  • ZHU WEIGUO
  • CHENG YONGXIAN
  • KANG TIANSHU
  • YAN YONGMING
  • LU XIAOPENG
  • HUANG JINBO

Assignees

  • 深圳大学

Dates

Publication Date
20260512
Application Date
20231012

Claims (6)

  1. 1. The application of a small molecular compound YZL-51N in preparing SIRT7 selective inhibitor is characterized in that the structural formula of the small molecular compound YZL-51N is as follows ; The SIRT7 selective inhibitors are useful in the treatment of colon cancer.
  2. 2. The use according to claim 1, wherein the small molecule compound YZL-51N specifically inhibits SIRT7 deacetylase activity in vitro.
  3. 3. The use according to claim 1, wherein the small molecule compound YZL-51N specifically binds to the active enzymatic central pocket of SIRT 7.
  4. 4. The use according to claim 3, wherein the amino acid of small molecule compound YZL-51N that has hydrogen bond interaction with the enzymatic active center pocket of SIRT7 comprises a combination of one or more of Asn297, gly268, leu298, thr112, asp118, cys315, gin 299, pro117, lys314, gly109, val296, ser 269.
  5. 5. The use according to claim 1, wherein the small molecule compound YZL-51N selectively inhibits SIRT7 activity and supplements a catalytic substrate of SIRT7 in cells.
  6. 6. The use of claim 5, wherein the catalytic substrate of SIRT7 comprises H3K18ac.

Description

Application of small molecular compound YZL-51N in preparation of SIRT7 selective inhibitor Technical Field The invention relates to the field of novel small molecular compounds and the field of pharmacy, in particular to application of a small molecular compound YZL-51N in preparation of SIRT7 selective inhibitors. Background The silencing informative regulator (Silent Information Regulator, sirtuins) is a family of evolutionarily highly conserved NAD + -dependent histone deacetylases. Among sirtuins family proteins of human origin, the gene sequence of SIRT7 was first reported in 2000. With the continued depth of research, researchers have found SIRT7 as an important target for a variety of cellular biological activities, such as rDNA stabilization and rRNA maturation, DNA damage repair, genomic stability and cell senescence, among others. Dysfunction of SIRT7, for example, can cause partial embryonic lethality, premature senility, fatty liver, and the like. SIRT7 also exhibits a high expression state in various malignant tumors such as colorectal cancer, pancreatic cancer, and breast cancer. SIRT7 is also involved in an important process of DNA damage repair in the nucleus. At the beginning of DNA damage, SIRT7 relies on PARP1 recruitment to the site of damage, post-deacetylation of the H3K18 site recruiting 53BP1 to participate in non-homologous end joining repair. Meanwhile, SIRT7 can dissuccinylate the H3K122 site, so that the chromatin structure is compact. At the end of DNA damage repair, SIRT7 deactivates ATM by deacetylating ATM, ensuring DNA damage repair is complete. Therefore, developing novel targeted SIRT7 small molecule inhibitors and achieving effective chemical intervention are of great biological significance. However, the existing targeted small molecule inhibitors of SIRT7 still have a number of problems. The development of SIRT7 inhibitors has been slow due to lack of suitable screening systems, detailed crystal structure and target selectivity analysis, and the like. For example, although the NAD + hydrolysate NAM is used to inhibit SIRT7 activity, its feedback inhibition mechanism allows NAM to inhibit all sirtuins proteins simultaneously. Compound ID 97491 is the first SIRT7 small molecule inhibitor screened from a library of compounds of known structure, however compounds lack selective assay validation and the existence of a controversial catalytic substrate. In addition, two reported SIRT7 cyclic peptide small molecule inhibitors were found to have SIRT1 and SIRT6 deacetylation inhibiting effects as well. The discovery of the newly reported compounds 2800Z and 40569Z compounds is too dependent on computer-aided screening and lack of experimental verification of drug interaction with the target. Thus, there is a need for improvements in the art. Disclosure of Invention In view of the shortcomings of the prior art, the invention aims to provide an application of a small molecular compound YZL-51N in preparing SIRT7 selective inhibitors, and aims to solve the problem of insufficient specificity of SIRT7 inhibitors in the prior art. The technical scheme of the invention is as follows: Application of small molecular compound YZL-51N in preparation of SIRT7 selective inhibitor, wherein the structural formula of the small molecular compound YZL-51N is The application, wherein the small molecule compound YZL-51N specifically inhibits the deacetylase activity of SIRT7 in vitro. The application, wherein the small molecule compound YZL-51N specifically binds to an enzyme activity center pocket of SIRT 7. The application, wherein the amino acid of the small molecule compound YZL-51N with hydrogen bond interaction with the enzyme active center pocket of SIRT7 comprises one or more of Asn297, gly268, leu298, thr112, asp118, cys315, gln299, pro117, lys314, gly109, val296 and Ser 269. The use wherein the small molecule compound YZL-51N selectively inhibits SIRT7 activity and supplements a catalytic substrate for SIRT7 in a cell. The use wherein the catalytic substrate of SIRT7 comprises H3K18ac. Application of small molecular compound YZL-51N in screening SIRT7 targeted drugs, wherein the structural formula of the small molecular compound YZL-51N is The use, wherein the medicament further comprises a pharmaceutically acceptable carrier and/or excipient. Application of small molecular compound YZL-51N in research of SIRT7-ATM molecular signal path, wherein the structural formula of the small molecular compound YZL-51N is The use wherein the small molecule compound YZL-51N interferes with the SIRT7-ATM molecular signaling pathway in a cell. The invention has the beneficial effects that the invention provides the application of the small molecular compound YZL-51N in preparing SIRT7 selective inhibitor. The invention detects that the small molecular compound has stronger binding force with SIRT7 through a biological membrane layer interference (BLI) experimental method. The compound can be combined