阅读说明：本技术 Pgam1别构抑制剂hkb99在制备治疗肺腺癌药物中的应用 (Application of PGAM1 allosteric inhibitor HKB99 in preparation of drugs for treating lung adenocarcinoma ) 是由 沈瑛 梁倩 陈红专 周璐 周烨 顾玮铭 罗鸣宇 于 2019-04-10 设计创作，主要内容包括：本发明提供PGAM1别构抑制剂HKB99在制备治疗肺腺癌药物中的应用,PGAM1别构抑制剂HKB99能够显著抑制肺腺癌及其耐药细胞增殖和迁移,且对正常支气管上皮细胞影响较小,具有良好的选择性；体内实验发现HKB99能抑制人肺腺癌皮下瘤生长和肿瘤转移。HKB99有望成为高效、低毒的抗肿瘤新药,为PGAM1抑制剂联合厄洛替尼治疗肺腺癌提供实验理论依据。(The invention provides an application of PGAM1 allosteric inhibitor HKB99 in preparation of a medicament for treating lung adenocarcinoma, and PGAM1 allosteric inhibitor HKB99 can obviously inhibit lung adenocarcinoma and proliferation and migration of drug-resistant cells thereof, has small influence on normal bronchial epithelial cells, and has good selectivity; in vivo experiments show that HKB99 can inhibit the growth of subcutaneous tumor of human lung adenocarcinoma and tumor metastasis. HKB99 is expected to become a novel high-efficiency and low-toxicity antitumor drug, and provides experimental theoretical basis for treating lung adenocarcinoma by combining PGAM1 inhibitor with erlotinib.)

Use of HKB99, an allosteric inhibitor of PGAM1, in the manufacture of a medicament for the treatment of lung adenocarcinoma, wherein HKB99 has the formula:

the application of the combination of the PGAM1 allosteric inhibitor HKB99 and an anti-lung adenocarcinoma drug in the preparation of the drugs for treating the lung adenocarcinoma is characterized in that HKB99 has the following structural formula:

3. the use of the PGAM1 allosteric inhibitor HKB99 in combination with an anti-lung adenocarcinoma drug according to claim 2 for the preparation of a medicament for the treatment of lung adenocarcinoma, wherein said anti-lung adenocarcinoma drug is erlotinib.

Technical Field

The invention relates to the technical and pharmaceutical chemistry field, in particular to application of PGAM1 allosteric inhibitor HKB99 in preparation of a drug for treating lung adenocarcinoma.

Background

Phosphoglycerate mutase 1 (PGAM 1) is an important enzyme in an aerobic glycolysis pathway of tumor cells, catalyzes a substrate 3-phosphoglycerate (3-PG) to be converted into 2-phosphoglycerate (2-PG), can regulate glycolysis rate, and participates in regulating a pentose phosphate pathway and a serine synthesis pathway by regulating the concentrations of 3-PG and 2-PG, so that the whole metabolic network is influenced. The PGAM1 expression and activity are abnormally increased, the PGAM1 plays an important role in the occurrence and development of various tumors, the PGAM1 inhibitor is expected to be a new anti-tumor target, and the design and screening of the PGAM1 inhibitor with high activity and high specificity are paid more and more attention by researchers.

Metabolic reprogramming is one of important characteristics of tumors, a plurality of metabolic pathways such as aerobic glycolysis, tricarboxylic acid cycle, oxidative phosphorylation and the like are obviously changed in the canceration process of cells, energy required by tumor growth can be provided, metabolic intermediates of the metabolic pathways also provide raw materials for synthesis of biological macromolecules such as protein, fat, nucleic acid and the like, the tumor formation depends on regulation of metabolic key enzymes, and the malignant potential is increased. The PGAM1 is in the midstream of glycolysis pathway, is highly expressed in various tumor tissues such as lung cancer, liver cancer, breast cancer, colorectal cancer, glioma and the like, the protein level of the PGAM1 is negatively correlated with the prognosis of a patient, and is positively correlated with the classification and severity of the tumor tissues, and the PGAM1 is expected to be a new anti-tumor target.

Evan et al first reported that small molecule compound MJE3 can specifically inhibit PGAM1, but the cell level inhibitory activity is weak. PGMI-004A obtained by screening Hitosugi and the like can selectively inhibit PGAM1 activity, obviously inhibit tumor cell proliferation and subcutaneous transplantation tumor growth, but the inhibition activity still needs to be further improved. The natural product EGCG separated from green tea by Xiaooguang Li and the like can inhibit the activity of PGAM1, but the specificity is poor, other action targets exist, and the in vivo experiment result is not reported. Therefore, research and development of more active and specific PGAM1 inhibitors have become hot spots for research of antitumor drugs.

Lung cancer is classified into non-small cell lung cancer (NSCLC, 80%) and small cell lung cancer (SCLC, 20%). The incidence of lung adenocarcinoma is rapidly increasing year by year, and the lung adenocarcinoma is the most common pathological type of NSCLC, accounting for about 50 percent. Most lung cancer patients enter the advanced stage or the late stage of the disease when the diagnosis is confirmed, the optimal operation chance is missed, the radiotherapy and chemotherapy are taken as the main treatment scheme, the effective response rate is low, and the toxic and side effect is high.

The first generation of EGFR-TKIs represented by erlotinib, gefitinib and afatinib greatly relieves the clinical symptoms of NSCLC patients with EGFR sensitive activating mutation (mainly comprising deletion mutation Del19 of exon 19 and missense mutation L858R of exon 21) and prolongs progression-free survival period. The NSCLC with positive EGFR sensitive mutation accounts for 30-40% in China, particularly more than 60% of lung adenocarcinoma, so that EGFR-TKIs have important significance in treating lung adenocarcinoma patients in China. However, in clinical practice, even if the drug is effective in the early stage of treatment, the drug resistance phenomenon occurs to different degrees 4-12 months after the treatment, and then the tumor relapse is caused, so that the TKIs are the biggest obstacle in clinical application.

Chinese patent application CN201810273938.9 discloses a 9, 10-anthraquinone compound or pharmaceutically acceptable salt thereof and pharmaceutical application thereof, wherein the structural formula of the 9, 10-anthraquinone compound is as follows:

the compounds can inhibit phosphoglycerate mutase activity and reduce cell metabolism level, and can be used for treating diseases such as solid tumor and blood tumor. Wherein HKB99 has the following chemical structural formula:

disclosure of Invention

The first purpose of the invention is to provide the application of the PGAM1 allosteric inhibitor HKB99 in the preparation of the drugs for treating lung adenocarcinoma.

The second purpose of the invention is to provide the application of the PGAM1 allosteric inhibitor HKB99 and an anti-lung adenocarcinoma drug in the preparation of drugs for treating lung adenocarcinoma.

In order to achieve the first object of the invention, the invention provides application of PGAM1 allosteric inhibitor HKB99 in preparation of a medicament for treating lung adenocarcinoma, wherein HKB99 has the following structural formula:

in order to achieve the second object, the invention provides application of a PGAM1 allosteric inhibitor HKB99 and an anti-lung adenocarcinoma drug in preparation of a drug for treating lung adenocarcinoma, wherein the HKB99 has the following structural formula:

as a preferred embodiment, the anti-lung adenocarcinoma drug is erlotinib.

The invention has the advantages that PGAM1 allosteric inhibitor HKB99 can obviously inhibit the proliferation and migration of lung adenocarcinoma and drug-resistant cells thereof, has small influence on normal bronchial epithelial cells, and has good selectivity; in vivo experiments show that HKB99 can inhibit the growth of lung adenocarcinoma subcutaneous tumor and tumor metastasis. HKB99 is expected to become a novel high-efficiency and low-toxicity antitumor drug, and provides experimental theoretical basis for treating lung adenocarcinoma by combining PGAM1 inhibitor with erlotinib.

Drawings

Figure 1 HKB99 selectively inhibits lung adenocarcinoma cell proliferation.

Figure 2. short-term treatment with low dose of HKB99 inhibited lung adenocarcinoma cell motility.

FIG. 3 HKB99 inhibits drug-resistant cell proliferation and motility, increasing sensitivity to erlotinib.

FIG. 4. effect of combined HKB99 on subcutaneous transplantation of PC9 cells.

FIG. 5 HKB99 inhibits HCC827-Luc tail vein injection in vivo transplantation.

Detailed Description

Hereinafter, the technique of the present invention will be described in detail with reference to specific embodiments. It should be understood that the following detailed description is only for the purpose of assisting those skilled in the art in understanding the present invention, and is not intended to limit the present invention.