Application of Hayatine and analogues thereof in preparation of mTORC1 inhibitor

文档序号：349876 发布日期：2021-12-07 浏览：23次中文

阅读说明：本技术 Hayatine及其类似物在制备mTORC1抑制剂中的应用 (Application of Hayatine and analogues thereof in preparation of mTORC1 inhibitor ) 是由葛欣王平路美玲王兴波于 2021-10-11 设计创作，主要内容包括：本发明涉及一种Hayatine及其类似物用于制备mTORC1抑制剂的应用。本发明使用多种方案确认了Hayatine抑制mTORC1的能力,还证实了Hayatine对氨基酸和葡萄糖诱导的mTORC1激活的抑制作用是由于Hayatine可导致mTORC1在溶酶体的定位下调。另外本发明揭示了Hayatine具有与mTORC1在溶酶体的定位蛋白(蛋白质复合物RagA/C)相互作用的结构新颖性,从而破坏了诱导细胞增殖的mTORC1信号,这使得Hayatine具有与当前热点抗癌药物-mTORC1抑制剂(雷帕霉素及其类似物)完全不同的机制独特性。(The invention relates to application of hayantine and analogues thereof in preparation of mTORC1 inhibitors. The ability of Hayatine to inhibit mTORC1 was confirmed using various protocols, and it was also confirmed that the inhibitory effect of Hayatine on amino acid and glucose-induced mTORC1 activation was due to the fact that Hayatine can cause the targeted down-regulation of mTORC1 at lysosomes. In addition, the invention discloses that hayantine has structural novelty in interaction with a lysosomal localization protein (protein complex RagA/C) of mTORC1, thereby disrupting mTORC1 signaling that induces cell proliferation, which makes hayantine have completely different mechanism uniqueness from current hotspot anticancer drugs, mTORC1 inhibitors (rapamycin and its analogs).)

1. the application of the compound shown in the formula I in preparing mTORC1 inhibitor,

wherein R1 and R6 are H or C1-C6 alkyl, said C1-C6 alkyl may be further substituted by halogen, hydroxy, amino, cyano, carboxy;

r2, R3, R4 and R5 are H, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, nitro, amino, halogen, cyano and carboxyl, wherein the C1-C6 alkyl can be further substituted by halogen, hydroxyl, amino, cyano and carboxyl; one or more substituents R2, R3, R4 and R5 may be present on the same benzene ring.

2. Use according to claim 1, characterized in that the compound of formula I interacts with the protein complex RagA/C.

3. Use according to claim 1, characterized in that the compound of formula I is hayantine.

4. Use of a compound of formula I in the manufacture of a medicament for the prevention and treatment of a disease mediated by mTOR, preferably a cancer or an immune-mediated disease, selected from brain and neurovascular tumors, head and neck cancer, breast cancer, lung cancer, mesothelioma, lymphoma, gastric cancer, kidney cancer, liver cancer, ovarian endometriosis, testicular cancer, gastrointestinal cancer, prostate cancer, glioblastoma, skin cancer, melanoma, neural cancer, spleen cancer, pancreatic cancer, blood proliferative disorders, lymphoma, leukemia, endometrial cancer, cervical cancer, vulval cancer, prostate cancer, penile cancer, bone cancer, muscle cancer, soft tissue cancer, intestinal or rectal cancer, anal cancer, bladder cancer, bile duct cancer, eye cancer, gastrointestinal stromal tumors, and neuroendocrine tumors; the immune-mediated disease is selected from the group consisting of resistance developed by transplantation of cells from the heart, kidney, liver, bone marrow, skin, cornea, lung, pancreas, small intestine, limb, muscle, nerve, duodenum, small intestine, or pancreatic islet; graft versus host disease caused by bone marrow transplantation; rheumatoid arthritis, systemic lupus erythematosus, hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, allergic encephalomyelitis and glomerulonephritis,

wherein R1 and R6 are H or C1-C6 alkyl, said C1-C6 alkyl may be further substituted by halogen, hydroxy, amino, cyano, carboxy;

5. Use according to claim 4, characterized in that the compound of formula I is Hayatine.

6. A pharmaceutical preparation for inhibiting mTORC1, comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable excipient,

wherein R1 and R6 are H or C1-C6 alkyl, said C1-C6 alkyl may be further substituted by halogen, hydroxy, amino, cyano, carboxy;

7. The pharmaceutical formulation of claim 6, wherein the compound of formula I is Hayatine.

8. The pharmaceutical formulation of claim 6, wherein the pharmaceutical formulation is suitable for gastrointestinal or parenteral administration.

9. The pharmaceutical preparation of claim 6, wherein the pharmaceutical preparation is a lyophilized preparation, an injection, a tablet, a granule or a capsule.

10. The pharmaceutical formulation of claim 6, wherein the compound of formula I interacts with the protein complex RagA/C.

Technical Field

The invention belongs to the technical field of new application of medicines, and particularly relates to application of hayantine and analogues thereof in preparation of a mTORC1 inhibitor.

Background

It is well known that the mTOR signaling pathway determines cell growth, proliferation, angiogenesis, protein translation, energy homeostasis, and lipid metabolism^[1,2]. mTOR exists in two complexes: mTOR complex 1(mTORC1) consisting of Raptor, LST8, PRAS40 and Deptor, regulates protein synthesis and corresponding cell proliferation by phosphorylation of p70S6K1 and 4E-BP1^[3]Whereas mTORC2 consists of Rictor, LST8, SIN1, Deptor and PRR5, regulates cell survival through phosphorylation of AKT/PKB^[4]As shown in fig. 1. Aberrant mTOR signaling has been reported to be closely associated with a variety of cancers, and has therefore attracted widespread interest as a hotspot therapeutic target for cancer therapy^[2]。

Rapamycin and its analogs (rapamyins/rapalogs) have received much attention because of their successful use in preclinical treatment for inhibiting mTORC1 activity and its associated specific cancers, and are a new focus of oncological drug therapy. Rapamycin and its analogues, however, have a typical transient response, with a subsequent marked rebound of tumor growth (a phenomenon known as rapamycin resistance), which is thought to be caused by inhibition of mTORC1 to compensate for the activation of mTORC 2-induced overactivation of AKT. Recent studies have shown that rapamycin and existing rapamycin analogues do not completely inhibit mTORC1 activity, and do not inhibit mTORC2, since treatment with rapamycin and analogues thereof often results in compensationOver-activation of the mTORC2-AKT protein kinase signaling pathway, thereby greatly reducing its benefit as an anti-cancer agent^[5]As shown in fig. 1. To address this problem, ATP-competitive mTOR inhibitors, such as selective mTOR inhibitors (e.g., OSI-027), have been used in clinical trials^[6]、INK-128^[7]And CC-223^[8]) And dual mTOR/PI3K inhibitors (e.g., PF-04691502)^[9]、BEZ235^[10]And GSK2126458^[11]) However, unexpected side effects including rash, weight loss, mucositis, depression, thrombocytopenia, hyperlipidemia, etc. have been observed, and together with their expensive preparation, which makes them difficult to generalize for clinical use, underscores the urgent need to identify novel mTORC1 inhibitors that are mechanistically distinct from rapamycin/analogs and ATP-competitive mTOR inhibitors.

Furthermore, current mTORC1 inhibitors, such as rapamycin and its chemical analogs, are artificially synthesized and face significant challenges from unavoidable cytotoxicity, even fatal consequences^[12]Accompanied by their incomplete and transient inhibitory effects on mTORC1 activity^[13]. As a result of the many important discoveries made from natural compounds, more effective and safer therapeutic drugs have been developed^[14]Therefore, the importance of finding new, safe antitumor drugs is increasing by selecting natural compounds that effectively inhibit mTORC1 signaling.

The mTORC1 signaling pathway plays a crucial role in cell growth^[15]Wherein mTORC1 promotes synthetic and metabolic processes by phosphorylation of ribosomal protein S6(rpS6) by pS6K^[16，17]. Increasing evidence suggests that phosphorylation of S6K, pS6K-T389, can represent activation levels of mTORC1 and is therefore accepted as a standard method for screening mTORC1 inhibitors^[18]Rather than the previous intracellular screening strategy of screening for modulators of mTORC1 by analyzing pS6 levels in target cells^[19]. Meanwhile, whole genome siRNA cell screening is carried out, and it is found that autophagy can cause reduction of mTORC1 in lysosome enrichment region, and then mTORC1 signal is inhibited^[20]. In addition, Meyer et al determined that GPR137B isA potential substrate that specifically interacts with Rag GTPases, thereby modulating lysosomal localization and activity of mTORC1^[21]Underscores the important role of autophagy in modulating mTORC1 activity. Thus, by analyzing the binding method of mTORC1 localization on lysosomes and pS6K-T389 phosphorylation in target cells, mTORC1 activity can be more accurately analyzed^[22]And make the same approach attractive for screening mTORC1 inhibitors. However, this method requires a long-term operation for detecting each compound, is expensive, and has a great influence on its large-scale application, so that it is necessary to develop a new compound screening method in a more economical and realistic manner.

Therefore, researchers in this field have employed another comprehensive approach (VS) to increase the efficiency of screening for mTORC1 inhibitors^[18]. They developed a screening model for identifying new structural analogues of mTORC1 inhibitors and found 15 new mTOR kinase inhibitors, including 4 compounds with potential for use (IC50 values below 10 μ M). In addition, they demonstrated that these compounds induce cell death by apoptosis through cell studies and western blot analysis, revealing the characteristics of these compounds with potential for clinical application^[18]However, the disadvantage of producing false positives is still evident^[23]This reflects the urgent need for efficient and accurate screening systems in the discovery of mTORC1 inhibitors, especially in natural compounds. Recently, studies have demonstrated that phosphorylated rpS6 determines the maintenance of cell size^[24]. Furthermore, Blenis et al reported that rapamycin/analogs and ATP-competitive binding PI3K/mTOR inhibitor LY294002 maintained its inhibitory effect on cell size in a pS 6K-dependent manner over 2-3 days^[25]This suggests that cell size may play a role in screening for natural mTORC1 inhibitory compounds.

Disclosure of Invention

In view of the above-mentioned drawbacks of the prior art, the present invention aims to provide the following solutions:

the application of the compound shown in the formula I in preparing mTORC1 inhibitor,

wherein R1 and R6 are H or C1-C6 alkyl, said C1-C6 alkyl may be further substituted by halogen, hydroxy, amino, cyano, carboxy;

Further preferred is the use, characterized in that the compound of formula I interacts with the protein complex RagA/C.

Further preferred is the use, wherein the compound of formula I is Hayatine.

The present invention also provides another technical means, the use of a compound of formula I in the manufacture of a medicament for the prevention and treatment of a disease mediated by mTOR, preferably a cancer or an immune-mediated disease, selected from brain and neurovascular tumors, head and neck cancer, breast cancer, lung cancer, mesothelioma, lymphatic cancer, stomach cancer, kidney cancer, liver cancer, ovarian endometriosis, testicular cancer, gastrointestinal cancer, prostate cancer, glioblastoma, skin cancer, melanoma, neural cancer, spleen cancer, pancreatic cancer, blood proliferative disorders, lymphoma, leukemia, endometrial cancer, cervical cancer, vulval cancer, prostate cancer, penile cancer, bone cancer, muscle cancer, soft tissue cancer, intestinal or rectal cancer, anal cancer, bladder cancer, bile duct cancer, eye cancer, gastrointestinal stromal tumor, and neuroendocrine tumor; the immune-mediated disease is selected from the group consisting of resistance developed by transplantation of cells from the heart, kidney, liver, bone marrow, skin, cornea, lung, pancreas, small intestine, limb, muscle, nerve, duodenum, small intestine, or pancreatic islet; graft versus host disease caused by bone marrow transplantation; rheumatoid arthritis, systemic lupus erythematosus, hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, allergic encephalomyelitis and glomerulonephritis,

wherein R1 and R6 are H or C1-C6 alkyl, said C1-C6 alkyl may be further substituted by halogen, hydroxy, amino, cyano, carboxy;

Further preferably, in the above application, the compound of formula I is Hayatine.

The invention also provides another technical scheme, a pharmaceutical preparation for inhibiting mTORC1, which is characterized by comprising a therapeutically effective amount of a compound shown as a formula I and pharmaceutically acceptable auxiliary materials,

wherein R1 and R6 are H or C1-C6 alkyl, said C1-C6 alkyl may be further substituted by halogen, hydroxy, amino, cyano, carboxy;

Further preferably, the compound of formula I in the pharmaceutical formulation is Hayatine.

Further preferably, the pharmaceutical preparation is a pharmaceutical preparation suitable for gastrointestinal or parenteral administration.

Further preferably, the pharmaceutical preparation is a freeze-dried preparation, an injection, a tablet, a granule or a capsule.

Further preferably, the compound of formula I interacts with the protein complex RagA/C in said pharmaceutical formulation.

Advantageous effects, the present invention uses various established protocols to confirm the ability of Hayatine to inhibit mTORC1, and also demonstrates that Hayatine's inhibitory effect on amino acid-induced mTORC1 activation is due to its role in the downregulation of mTORC1 translocation to lysosomes. Importantly, hayantine was found to have structural novelty in its interaction with the protein complex RagA/C, disrupting the normal mTORC1 signal, which makes hayantine completely different from current mTORC1 inhibitors in mechanism uniqueness. Furthermore, this remarkable feature of Hayatine targeting mTORC1 signaling complex rather than mTOR itself may prevent the adverse effects of compensatory mTORC2-AKT signaling on tumor treatment.

Description of the drawings:

FIG. 1 is a diagram showing the mechanism of action of Hayatine and Rapamycin.

FIG. 2 shows the compound screening process and the results of the effect of Hayatine on cells.

Fig. 3 is a graph of the effect of Hayatine on mTORC1 signaling.

FIG. 4 shows the effect of Hayatine on HCT116 cells.

Fig. 5 is a graph of the effect of Hayatine on amino acid-induced activation of mTORC 1.

FIG. 6 is the analysis of the action mechanism of Hayatine.

Detailed Description

The present invention is further described below with reference to specific examples, which are only exemplary and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.

The technical solution of the present patent will be described in further detail with reference to the following embodiments.

Example 1 screening of natural mTORC1 inhibitors

A in figure 2 gives the virtual screening process,a cell size dependent selection model was established to predict mTORC1 inhibitors, with 141 natural compounds combined with various classification methods to screen mTORC1 inhibitors. To avoid digestive enzymes and other factors that may affect drug selection, compound identification was performed using suspended B lymphocytes from multiple myeloma (H929). A total of 141 molecules were used for H929 cells, and to exclude false positives 5 compounds (labeled #11, #17, #48, #153, #159) (fig. 2B) were selected, requiring an inhibition of the function associated with mTORC1 activity of more than 20% according to a defined criterion^[18]. In order to avoid acute cytotoxic effects affecting cell size, in the above compound selection, the cell death rate at 48 hours after compound treatment was compared, and it was found that compound Hayatine, labeled #48, was able to significantly change cell size without triggering cell death (C in fig. 2 and D in fig. 2). Subsequently, it was investigated whether Hayatine also affects the cell size of adherent tumor cells, such as human large intestine tumor cells (HCT 116). H flow cytometry results confirmed that Hayatine had a significant effect of changing cell size in both suspension and adherent cells (E in fig. 2 and F in fig. 1).

Example 2 Effect of Hayatine on mTORC1 Signal transduction

To evaluate the effect of Hayatine on mTORC1 signaling, it was tested whether Hayatine could act as a potential mTORC1 inhibitor by examining pT389-S6K protein expression and mTORC 1-induced autophagy. The inhibitory activity of Hayatine on mTORC1 kinase in H929 and HCT116 cells was determined by S6K phosphorylation activity using pT389-S6K protein as a substrate for specific mTORC1 (a in fig. 3 and B in fig. 3). As shown in fig. 3C, treatment with Hayatine resulted in a dose-dependent inhibition of mTORC1 activity, indicating Hayatine is a potent mTORC1 inhibitor. To test whether Hayatine affects mTORC1 activity-related function, we measured the autophagy numbers of HCT116 cells using a fluorescently labeled LC3 indicator system, which is based on a clear aggregation phenomenon of LC3 during autophagy formation, since LC3 protein typically diffuses in the cytoplasm to form several bright green fluorescent spots on the cell membrane when autophagy occurs. Since the accepted concept that the fluorescence intensity of the LC3 protein is equivalent to the intensity of autophagy activity, we evaluated the amount of autophagy by calculating the fluorescence intensity through software, and found that Hayatine can significantly induce autophagy (D in fig. 3 and E in fig. 3). The results of protein quantification also demonstrate the up-regulation effect of Hayatine in the induction of autophagy, which was specifically blocked by the autophagy inhibitor bafilmycin a1 (F in fig. 3, G in fig. 3, and H in fig. 3).

Example 3 hayantine inhibits growth and cell migration of cancer cells.

Other mTORC1 activities such as controlling cell growth and migration are also strongly associated with tumor progression. To further confirm that Hayatine is a potent mTORC1 inhibitor, we performed the following experiments. First, we examined the effect of Hayatine on HCT116 cell growth. Our results show that Hayatine significantly inhibited cell growth of HCT116 in both cell proliferation assays (a in fig. 4) and colony formation assays (B in fig. 4 and C in fig. 4). Subsequently, we performed wound healing experiments and found that Hayatine blocked cell migration in a dose-dependent manner (D in fig. 4 & E in fig. 4), suggesting that Hayatine plays a key role in down-regulating tumor mTORC1 activity.

Example 4Hayatine blocks amino acids induced mTORC1 activation.

The tumor mTORC1 activity is closely related to environmental stimulating factors (including glucose, insulin and amino acids) as reported^[16]Therefore, we further investigated whether Hayatine is involved in environmental factor-induced mTORC1 activation. For this reason, the above-described mTORC1 activity-related factors were tested separately. Our data show that Hayatine strongly reduces phosphorylation of S6, thereby attenuating mTORC1 activation under amino acid or glucose treatment (a in fig. 5, B in fig. 5, C in fig. 5, and D in fig. 5), in contrast to Hayatine which has no significant change upon insulin treatment (E in fig. 5 and F in fig. 5), suggesting that Hayatine acts as a negative regulator in amino acid-induced mTORC1 activation. To further investigate the role of Hayatine in the inactivation of mTORC1, we imaged immunofluorescence images of HCT116 cells under amino acid stimulation, in parallel with Hayatine treatment. Our results show that Hayatine significantly inhibited amino acid-induced transport of mTORC1 to lysosomes (G in fig. 5)&H in FIG. 5)This is consistent with previous reports that lysosome transport is closely related to activation of mTORC1^[20]。

Example 5 analysis of the Hayatine mechanism of action

Further performing structural novelty and drug similarity analysis. The chemical structure of Hayatine is shown as a in fig. 6. To evaluate the novelty of hit associated with known mTORC1 kinase inhibitors (e.g., rapamycin), rapamycin was reported to inhibit mTORC1 activity by recruiting FKBPs to mTOR (B in fig. 6), we used a docking modality (http:// zdock. umassmed. edu) to predict the binding modality of hayantine to the RagA/C-LAMTOR complex (6EHR) required by RAPTOR to recruit mTORC1 to the lysosome. To our surprise, hayantine demonstrated significant differences from currently known mTORC1 inhibitors by acting as a linking ligand between mTORC1 complex and its downstream signaling complex RagA/C, but rather than directly interacting with mTOR as rapamycin and its analogs inhibited mTORC1 signaling (C in fig. 6-E in fig. 6). Data from co-immunoprecipitation experiments further confirmed that Hayatine disrupted the protein association between RagC and RAPTOR, blocking mTORC1 downstream signaling (F in fig. 6). These results indicate that Hayatine's discovery provides a new mechanism for mTORC1 inhibition and a valuable option for further optimization of clinical applications.

As can be seen from a combination of the above experimental results, a variety of established protocols have been used to confirm the ability of Hayatine to inhibit mTORC1 (fig. 3 and 4). We also demonstrated that the inhibitory effect of Hayatine on amino acid-induced mTORC1 activation is due to its role in the downregulation of mTORC1 translocation to lysosomes (fig. 5). Importantly, we found that Hayatine has a structural novelty in its interaction with the protein complex RagA/C, disrupting the normal mTORC1 signal (fig. 6), which makes Hayatine completely different from current mTORC1 inhibitors in mechanism uniqueness. Furthermore, this remarkable feature of Hayatine targeting the mTORC1 signaling complex rather than mTOR itself can prevent the adverse effects of compensatory mTORC2-AKT signaling on treatment, i.e., effectively overcoming the difficulties of rapamycin resistance in current clinical applications (fig. 1).

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