阅读说明：本技术 Yg1702在制备aldh18a1特异性抑制剂中的应用 (Application of YG1702 in preparation of ALDH18A1 specific inhibitor ) 是由 余时沧 郭玉峰 段江洁 于 2018-05-29 设计创作，主要内容包括：本发明涉及一种YG1702在制备ALDH18A1特异性抑制剂中的应用,YG1702能够与ALDH18A1重组蛋白特异性结合,抑制其酶活性,并且抑制ALDH18A1后能够显著降低MYCN表达和NB细胞的成瘤能力及荷瘤小鼠的生存时间,可以作为治疗MYCN扩增的神经母细胞瘤的药物,为临床神经母细胞瘤的治疗提供了新的药物。(The YG1702 can be specifically combined with ALDH18A1 recombinant protein to inhibit the enzymatic activity of the ALDH18A1, and the inhibiting effect of the ALDH18A1 can obviously reduce the MYCN expression, the nodulation capacity of NB cells and the survival time of tumor-bearing mice, can be used as a medicine for treating MYCN-amplified neuroblastoma, and provides a new medicine for treating clinical neuroblastoma.)

Use of YG1702 in the preparation of a specific inhibitor of ALDH18A 1.

Use of YG1702 in the preparation of a reagent for inhibiting the function of ALDH18A1 protein.

Use of YG1702 in the preparation of a MYCN inhibitor.

Use of YG1702 in the preparation of a reagent for inhibiting MYCN mRNA and protein expression.

the application of YG1702 in preparing medicine for treating tumor with high ALDH18A1 expression.

Use of YG1702 in the manufacture of a medicament for the treatment of MYCN-amplified tumors.

The application of YG1702 in preparing medicine for treating neuroblastoma with high ALDH18A1 expression.

8. Use according to claim 7, characterized in that: YG1702 application in preparing the medicament for inhibiting ALDH18A1 high expression neuroblastoma proliferation, balling capacity, self renewal or growth.

9. Use according to claim 7, characterized in that: YG1702 application in preparing the medicament for prolonging the survival time of neuroblastoma with high ALDH18A1 expression.

Use of YG1702 in the manufacture of a medicament for the treatment of MYCN-expanded neuroblastoma.

11. Use according to claim 10, characterized in that: use of YG1702 in the preparation of a medicament for inhibiting the proliferation, balling-up, self-renewal or growth of MYCN-amplified neuroblastoma.

12. Use according to claim 10, characterized in that: use of YG1702 in the manufacture of a medicament for prolonging the survival of MYCN-expanded neuroblastoma.

Technical Field

The invention belongs to the field of biological medicines, and relates to application of YG1702 in preparation of an ALDH18A1 specific inhibitor.

Background

The acetaldehyde dehydrogenase 18A1(aldehyde dehydrogenase 18A1, ALDH18A1) gene encodes pyrroline-5-carboxylate synthase (P5 CS), which is involved in the metabolism of glutamic acid and proline, is a key enzyme catalyzing the synthesis of proline, ornithine and arginine, and plays an important role in the interconversion of proline, ornithine and glutamic acid and the metabolism of non-essential amino acids. Among them, glutamate-glutamine metabolism is an important energy metabolism mode of tumor cells in addition to the Warburg effect, and is an indispensable material basis for anabolism of tumor cells. The existing research reports that ALDH18A1 has high expression in glioma, prostatic cancer, pancreatic cancer, ovarian cancer, lung cancer, liver cancer, stomach and medulloblastoma, and is closely related to invasion, metastasis and poor prognosis of the tumors. Therefore, screening of specific inhibitors of ALDH18a1 is of great significance for the treatment of various tumors, especially MYCN-amplified tumors such as Neuroblastoma (NB).

Disclosure of Invention

In view of the above, an object of the present invention is to provide an application of YG1702 in the preparation of an ALDH18a1 specific inhibitor; the second object of the present invention is to provide the use of YG1702 in the preparation of a reagent for inhibiting MYCN mRNA and protein expression; the third objective of the present invention is to provide the use of YG1702 in the preparation of MYCN inhibitors; the fourth objective of the present invention is to provide the use of YG1702 in the preparation of reagents for inhibiting MYCN mRNA and protein expression; the fifth purpose of the present invention is to provide the application of YG1702 in the preparation of the medicine for treating the tumor with high ALDH18A1 expression; the sixth purpose of the present invention is to provide the application of YG1702 in the preparation of drugs for treating MYCN amplified tumors; the seventh purpose of the present invention is to provide the application of YG1702 in the preparation of the medicine for treating the neuroblastoma with high ALDH18A1 expression; the eighth object of the present invention is to provide the use of YG1702 in the preparation of a medicament for the treatment of MYCN-amplified neuroblastoma.

In order to achieve the above purpose, the invention provides the following technical scheme:

Use of YG1702 in the preparation of a specific inhibitor of ALDH18A 1.

Use of YG1702 in the preparation of a reagent for inhibiting the function of ALDH18A1 protein.

Use of YG1702 in the preparation of a MYCN inhibitor.

Use of YG1702 in the preparation of a reagent for inhibiting MYCN mRNA and protein expression.

The application of YG1702 in preparing medicine for treating tumor with high ALDH18A1 expression.

Use of YG1702 in the manufacture of a medicament for the treatment of MYCN-amplified tumors.

The application of YG1702 in preparing medicine for treating neuroblastoma with high ALDH18A1 expression.

Preferably, YG1702 is used for preparing the medicine for inhibiting the proliferation, balling capacity, self-renewal or growth of neuroblastoma with high ALDH18A1 expression.

Preferably, YG1702 is used for preparing the medicament for prolonging the survival time of neuroblastoma with high ALDH18A1 expression.

Use of YG1702 in the manufacture of a medicament for the treatment of MYCN-expanded neuroblastoma.

Preferably, YG1702 is used for the preparation of a medicament for inhibiting MYCN-amplified neuroblastoma proliferation, balling capacity, self-renewal or growth.

Preferably, YG1702 is used in the preparation of a medicament for prolonging the survival of MYCN-expanded neuroblastoma.

The invention has the beneficial effects that: the invention discloses application of YG1702 in preparation of an ALDH18A1 specific inhibitor, provides a new compound for regulation and control of ALDH18A1, and simultaneously YG1702 can also inhibit MYCN mRNA and protein expression, inhibit proliferation, balling-up capability and self-renewal of neuroblastoma and provide a new medicine for YG1702 to treat the neuroblastoma amplified by MYCN.

Drawings

In order to make the object, technical scheme and beneficial effect of the invention more clear, the invention provides the following drawings for explanation:

FIG. 1 is a data set of GSE16476 (FIG. 1, A), GSE13136 (FIG. 1, B), GSE12460 (FIG. 1, C) and E-MEXP-669 (FIG. 1, D) with MYCN amplification differentially expressing genes from non-amplified patients.

FIG. 2 is a GSE45547 dataset with MYCN amplified versus non-amplified patient differentially expressed genes.

FIG. 3 is an E-MTAB-161 (FIG. 3, A), E-MTAB-179 (FIG. 3, B), E-MTAB-1781 (FIG. 3, C), cancer cell encyclopedia data set (FIG. 3, D), MYCN amplified versus non-amplified patient differentially expressed genes.

Fig. 4 shows that the expression of ALDH18a1 was significantly enriched with MYCN target genes, genes positively associated with MYCN amplification, genes in a co-amplified state of MYCN (fig. 4, a), ALDH18a1 was highly expressed in MYCN-amplified cell lines (fig. 4, B), and ALDH18a1 was highly expressed in NB-amplified patients (fig. 4, C and D).

FIG. 5 is a graph of the effect on MYCN expansion and non-expansion NB cell proliferation (FIG. 5, A), balling (FIG. 5, B), symmetric division (FIG. 5, C and D), self-renewing genes (FIG. 5, E), tumorigenic capacity following intervention with ALDH18A1 (FIG. 5, F)

FIG. 6 shows the results of screening (FIGS. 6, A and B), identification (FIG. 6, C), structural formula (FIG. 6, D), binding pattern (FIGS. 6, E and F), and identification of specific binding (FIG. 6, G) of YG1702, a specific inhibitor of ALDH18A 1.

Figure 7 is a graph of the effect of the specific inhibitor of ALDH18a1, YG1702, on MYCN expansion in NB cells MYCN expression (fig. 7, a-D), spheronization capacity (fig. 7, E), cell viability (fig. 7, F), proliferation (fig. 7, G), body weight (fig. 7, H), tumorigenicity (fig. 7, I and J), and tumor-bearing mouse survival time (fig. 7, K).

Detailed Description

Preferred embodiments of the present invention will be described in detail below with reference to the accompanying drawings.