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A collection of novel drug targets

 Last Update: 2022-11-26
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This article summarizes the emerging targets of recent drug development, covering glioblastoma, pancreatic cancer, gastric cancer peritoneal metastases, small cell lung cancer, lupus nephritis, obesity, osteoarthritis, hypertension, drug-induced liver injury, non-alcoholic fatty liver disease, etc.
, which are generally newly reported new targets with certain therapeutic potential, in order to provide reference for researchers
.

overview

The discovery of novel targets is key
to drug discovery.
This article summarizes the recent R&D progress of novel drug targets reported in internationally renowned journals (Table 1), and describes the R&D progress
of drug candidates for different targets with reference to the database.

Table 1: List of recently reported novel drug targets

HECTD3

Glioblastoma (GBM) is the most common and deadly primary brain tumor in adults, and treatment for glioblastoma is still limited
due to drug delivery problems and the lack of characteristic molecular targets.
Ubiquitination is a post-translational modification of proteins that plays a key role
in cell fate determination, cell growth, and signal transduction.
The ubiquitination of proteins is catalyzed by the corresponding ubiquitin-related enzymes, E3 ubiquitin ligase HECTD3 is homologous to HECT-type ubiquitin ligases, and recent research results have shown that HECTD3 is highly expressed in ovarian cancer, breast cancer and esophageal squamous cell carcinoma, suggesting that it may play an important role
in tumorigenesis and development.
However, the specific biological function that HECTD3 plays in GBM is currently unclear
.
Recently, Professor Cui Hongjuan from the Medical Research Institute of Southwest University and Professor Liang Ping from Chongqing Medical University collaborated on British The Journal of Cancer publishes important research (Ref 1), elucidating the catalytic effect of HECTD3 in GBM on poly-ADP ribose polymerase 1 (PARP1) polyubiquitination and the regulatory effect on EGFR-mediated signaling pathway, which may provide a new characteristic target for the treatment and diagnosis of GBM
.
In order to explore the specific mechanism of HECTD3 promoting GBM proliferation, the researchers used mass spectrometry to analyze the interaction proteins of HECTD3, and the results showed that there may be a direct interaction
between HECTD3 and PARP1.
As an important molecule present in nucleoli, PARP1 plays a key role
in maintaining genome stability, replication, transcription, and other processes.
Therefore, the researchers speculate that the interaction between HECTD3 and PARP1 may be a key cause
of its carcinogenic effects.
In conclusion, this study explores the polyubiquitination of HECTD3 on PARP1, which has the potential to provide new effective targets for the treatment of brain tumors including GBM due to the pleiotropic role of PARP1 in
tumors.
It is hoped that further elucidating of HECTD3 function and further experiments on related targeted drugs in the future will bring good news
to more GBM patients.

DDX58

Lupus nephritis (LN) is the most common complication of systemic lupus erythematosus (SLE), with complex and diverse clinical manifestations, and heterogeneous treatment effects and prognosis
.
Genetic variation is the underlying cause
of LN occurrence and clinical phenotypic heterogeneity.
It is an important way
to analyze the new mechanism of LN occurrence and development from the perspective of genetic variation and explore new intervention targets and therapeutic methods.

On October 20, 2022, the team of academician Liu Zhihong of the National Clinical Research Center for Kidney Disease of the Eastern Theater General Hospital was presented at the Journal of the American Society of The article "A New DDX58 Pathogenic Variant Causes Lupus Nephritis Due to" was published in the journal Nephrology RIG-I Hyperactivation and its Clinical Implication”（Ref 2), using the whole exome sequencing analysis data of Chinese patients with special types of LN, the genetic mutation of DDX58 gene was discovered, and on the basis of elucidating the pathogenic mechanism of LN caused by overactivation of the IFN-I pathway; Proven to be effective in therapeutic action with targeted interventions
.
While analyzing the new gene of LN pathogenic and elucidating its molecular mechanism, this study provides a strong basis
for future LN targeted intervention based on molecular mechanism.

The pathogenesis of LN is complex, with strong clinical heterogeneity and different treatment
responses.
Genetic variation plays a decisive role
in the development of LN.
Patients with special types of LN have an early age of onset, a family history of SLE, and some special clinical manifestations such as epilepsy and psoriasis, which indicate that they have a special genetic background
.
Based on this, Academician Liu Zhihong's team started from special types of LN patients, conducted whole exome sequencing studies on 1376 patients, and found that there was a common gene mutation - DDX58 in 5 special types of LN families R109C, and further bioinformatics analysis confirmed that it may be a new LN pathogenic mutation
.

The mechanistic study found that DDX58 The R109C mutation can uninhibit the RIG-I protein, upregulate the K63 ubiquitination level of the RIG-I protein, promote the formation of oligomers of the RIG-I protein, enhance the interaction with downstream MAVS, and promote MAVS aggregation, thereby activating the RIG-I-MAVS-mediated type I interferon signaling pathway leading to kidney damage
.
The study was based on the whole exome sequencing data of the families of special types of LN patients and discovered a new pathogenic mutation of LN, DDX58 R109C, based on the elucidating of its pathogenic mechanism, demonstrates the effectiveness of
targeted interventions.
It provides an important basis
for the future development of accurate diagnosis and individualized treatment of LN based on molecular mechanism.

MSRA

Reactive oxygen species (ROS) are closely related to tumor progression, and studies have shown that pancreatic cancer will have highly complex redox signal transduction during progression, however, it is unknown whether different redox mechanisms are related to the strong metastasis ability of pancreatic cancer
.
In redox reactions, cysteine residues in proteins act as "switches", and previous studies have shown that cysteine oxidation can inhibit the development of pancreatic cancer, so this protein-based redox signaling may play an important role
in the malignant function of pancreatic cancer.
At present, most of the research on protein redox signaling focuses on cysteine, but less attention is paid to the reversible oxidation of another sulfur-containing amino acid, methionine
.
Methionine is closely related to the metabolism of various sulfur-containing compounds in organisms and has been shown to be related to
redox reactions in some physiological processes.
Methionine sulfoxide reductase A (Methionine sulfoxide reductase A,MSRA) is a methionine-related oxidoreductase that is also significantly associated
with a variety of pathological changes.
However, it is unclear whether methionine residues can also act as a "switch" for redox reactions and regulate the progression
of pancreatic cancer.

Recently, a research team from the Cancer Genetics Institute of Columbia University published an important research result in Molecular Cell, revealing the relationship between methionine oxidation and pancreatic cancer metastasis (Ref 3）
。 The study found that the methionine oxidative inhibitor MSRA inhibited the metastasis of pancreatic cancer and revealed the key molecular mechanism
of MRSA deletion to promote pancreatic cancer metastasis.
In conclusion, this study reveals new mechanisms of pancreatic cancer metastasis and develops key molecules
that can inhibit pancreatic cancer metastasis.

To determine whether methionine-based redox signaling affects the metastatic ability of pancreatic cancer, the researchers explored the effect
of MSRA, a key enzyme that inhibits methionine oxidation, on pancreatic cancer metastasis.
Through sample validation (clinical samples and mouse models), gene editing of organoids and mouse pancreatic tumor cells, and pancreatic cancer liver metastasis models, the researchers found that there was no significant difference in MSRA transcription levels and significantly reduced
protein stability in metastatic samples.
The study also found that organoid, cellular, and liver metastasis models that knocked out MSRA showed greater metastasis ability, so the deletion of MSRA significantly promoted pancreatic cancer metastasis
.

The researchers found higher levels of mitochondrial oxidation in metastatic pancreatic cancer organoids, but no changes in mitochondrial oxidation levels were found after knocking out MSRA, suggesting that the loss of MSRA did not affect the level of reactive oxygen species in primary pancreatic cancer and did not activate the signaling pathways
associated with metastasis.
Therefore, MSRA may control pancreatic cancer metastasis
by affecting protein oxidation states.
The researchers found higher levels of mitochondrial oxidation in metastatic pancreatic cancer organoids, but no changes in mitochondrial oxidation levels were found after knocking out MSRA, suggesting that the loss of MSRA did not affect the level of reactive oxygen species in primary pancreatic cancer and did not activate the signaling pathways
associated with metastasis.
Therefore, MSRA may control pancreatic cancer metastasis
by affecting protein oxidation states.
The researchers found that the loss of MSRA did not cause a change in the rate of extracellular acidification, but the content of pyruvate labeled by the 13C isotope increased significantly, while the glycolysis intermediate did not
.
Therefore, the loss of MSRA promotes oxidative phosphorylation of glucose in pancreatic cancer, not the classical glycolysis pathway
.
In addition, MSRA-dependent increased oxygen consumption and cell migration capacity have been shown in metastatic
pancreatic cancer.

Considering that pyruvate kinase M (PKM) is a key enzyme that catalyzes the conversion of phosphoenolpyruvate and ADP to pyruvate and ATP, combined with the effect of MSRA deletion on pyruvate conversion and the proteomics of reactive methionine, the researchers identified PKM as the main target of MSRA-mediated glucose metabolism
.
In addition, the researchers found that MSRA deletion did not cause a change in PKM protein expression, but increased the methionine oxidation state of PKM and increased the enzymatic activity
of the pyruvate kinase PKM.
The researchers further explored the effect of MSRA on PKM1 and PKM2, the two products encoded by PKM, and found that the deletion of MSRA increased the enzymatic activity of PKM2 instead of PKM1, and that the regulatory effect of MSRA on PKM2 was due to MSRA directly regulating methionine oxidation
of PKM2 。 In order to further clarify the molecular mechanism of MSRA regulating the oxidation of PKM2 methionine, the researchers analyzed six methionine residues on PKM2 sensitive to redox in proteomics, and found that only the redox state of methionine M239 changed significantly in primary and metastatic pancreatic cancer organoids
.
In addition, MSRA-mediated PK2 oxidation was found to promote the formation of highly active tetramers of PKM2, a phenomenon observed only in wild-type PKM2 but not in M239-mutated PKM2
.
Therefore, the researchers believe that the oxidative state of PKM2-M239 regulates the enzymatic activity
of PKM2 in an MSRA-dependent manner.
The researchers found that the use of TEPP46, a pharmacological activator of PKM2, significantly promoted the migration ability of pancreatic cancer cells, and TEPP46 treatment significantly improved the recurrence rate of tumors after resection and the ability
of liver metastasis in mouse models of pancreatic cancer.

In conclusion, this study found that the deletion of MSRA promotes pancreatic cancer metastasis, which is dependent on the oxidation of the PKM2 methionine M239 site, and the activation of PKM2 with pharmacological activators can significantly promote pancreatic cancer metastasis
.
Therefore, this study proves the important role of methionine oxidation in pancreatic cancer metastasis, clarifies its specific molecular regulatory mechanism, and identifies the key target MSRA and downstream key molecule PKM2 affecting pancreatic cancer metastasis, which provides a new strategy
for the targeted therapy of pancreatic cancer metastasis.

SOX9

Gastric cancer is one of the common digestive tract tumors, and in 2020, gastric cancer ranked fourth among the number of deaths from malignant tumors worldwide
.
90~95% of gastric cancers are gastric adenocarcinoma (GAC), unfortunately, often more than half of patients are diagnosed with GAC at an advanced stage and the survival period is less than six months
.
In addition, patients with advanced GAC are also extremely prone to peritoneal metastases, and there is currently a lack of effective targeted or immunotherapy drugs
for GAC peritoneal metastases.

The tumor microenvironment (TME) of GAC is highly heterogeneous
.
The presence of cancer stem cells (CSCs) in TME can regulate the function of a variety of immune cells in the microenvironment, thereby participating in tumor proliferation and invasion, promoting tumor recurrence and metastasis, and leading patients to resistance to conventional treatment and poor prognosis
.
The SOX family is an important class of stem cell transcription factors, some of which have been reported to be associated with
tumorigenesis and metastasis.
Sex-determining region Y-box protein 9 (Sex determining region Y box protein 9, SOX9) has been found to be highly expressed in a variety of malignant tumors and exerts carcinogenic effects
.
However, in GAC peritoneal metastases, the expression of SOX9 in tumor cells, the mechanism that promotes disseminated metastasis, and the specific role of immunosuppressive function in the microenvironment are unclear
。 Recently, Jaffer from the University of Texas MD Anderson Cancer Center A research team led by Ajani and Shumei Song published important findings (Ref) in Gut 4), it was found that the up-regulated SOX9 gene expressed in GAC can regulate the paracrine LIF factor of tumor cells and inhibit intratumoral CD8 T cells respond to and regulate macrophage function, thereby exerting immunosuppressive effects
.
More importantly, the combination targeting of the LIF/LIFR pathway and macrophage surface receptor CSF1R has great therapeutic potential for SOX9-mediated stem tumor cells, T cell immunosuppression and tumor metastasis, and may become a new drug therapy
for advanced GAC.

In order to explore the role of SOX transcription factor family in GAC peritoneal metastases, the research team performed single-cell sequencing on peritoneal metastatic tissues of 20 GAC patients, and found that SOX9 and SOX2 were highly enriched in tumor cell clusters, and higher expression levels also indicated shorter survival of patients
.
However, by further analysis of gastric cancer TCGA data and tissue staining of validation cohort samples, it was found that only SOX9 was significantly higher in tumor tissue expression than in normal or paracancerous tissue
.
At the same time, gastric cancer patients with high expression of SOX9 also showed shorter survival
.
In addition, immunofluorescence staining found that SOX9 was abundant in the nuclei of malignant tumor cells and low in immune cells in the tissues of carcinoma in situ or peritoneal metastases in GAC patients
.

In order to further explore the regulatory effect of SOX9 on CSCs in GAC peritoneal metastases, the research team analyzed the sequencing data of GAC peritoneal metastases samples and found that SOX9 and some other CSC-related genes were clustered in the
same tumor cell population.
CSCs are a group of cells that retain the characteristics of stem cells
and have the ability to self-renew.
Two GAC peritoneal metastases cell lines GA0518 and AGS were knocked out (KO) with SOX9 compared to control cells The self-renewal ability of KO tumor cells is significantly weakened, SOX9 The tumorigenic ability and metastatic diffusion ability of KO cells in xenograft model mice were significantly reduced
.
After confirming the important role of SOX9 in maintaining the stemness, aggressiveness and promotion of disseminated metastasis of GAC tumor cells, the research team wanted to further explore the potential role of
SOX9 in the tumor immunosuppressive microenvironment.
First, TCGA data from gastric cancer were analyzed and SOX9 and CD8 were found T cell infiltration or CD3D and CD8A expression were inversely correlated
.
Next, set the GA0518 SOX9 KO cells, GA0518 control cells, and peripheral blood mononuclear cells (PBMCs) from GAC patients were co-cultured
.
Flow cytometry found that PBMCs were associated with GA0518 SOX9 compared to control cells The number of CD8 T cells and the expression of effector molecules (granzyme B, perforin, and interferon γ) were increased
during co-culture of KO cells.
Also, with SOX9 After the culture supernatant of KO pretreated PBMCs with PBMCs the killing ability of T cells to target cells (GA0518-Luc) was also enhanced
.
These results suggest that SOX9 may regulate the secretion of certain factors by tumor cells, thereby inhibiting CD8 Cytotoxic activity
of T cells.

The research team found that in SOX9 In KO cells, LIF was one of the genes with the highest degree of down-expression, and GAC patients with higher LIF expression also showed shorter survival
.
LIF is a member of the IL-6 family, and studies have confirmed that LIF can activate signaling pathways in tumor cells through its receptors LIFR and GP130 and exert tumorigenic effects
.
In order to further verify the correlation between the expression of SOX9 and LIF, tumor samples from patients with GAC peritoneal metastases were tested and found that SOX9 and LIF were co-expressed on tumor cells, and LIF levels in ascites were significantly increased, while patients with higher LIF levels had shorter
survival.
These results indicate that SOX9-regulated LIF is also a poor prognostic indicator
for GAC peritoneal metastases.

Tumor-associated macrophages (TAMs) are key immune cell mediators
in TME that interact with CSCs and participate in tumor metastasis.
TAMs are mainly divided into M1 macrophages that play a pro-inflammatory role and M2 macrophages
that play an immunosuppressive role.
By analyzing the single-cell sequencing data of patients with GAC peritoneal metastases, it was found that the enrichment of macrophages within the tumor was related to the survival of the patients, and CD163 M2 macrophages also express high levels of CSF1R, CCL2 and IL10
.
With SOX9 Supervised supernatant pretreatment of M1 macrophages (induced differentiation by U937 monocytes) in KO cell culture found significant reductions in macrophage CCL2 and IL-10 (cytokines secreted by two M2 macrophages and mediated by immunosuppression), and the use of LIF/LIFR inhibitors (EC359) similarly reduced CCL2 and IL-10 levels
.
In addition, CSF1R inhibitor (PLX3397) can also inhibit CCL2 expression
.
These results indicate that SOX9 regulates the expression of LIF, which can indeed promote the differentiation and production
of M2 macrophages in the microenvironment.

What's more, LIF/LIFR inhibitors (EC359) can also restore the killing function
of CD8T cells in GAC peritoneal metastases.
TAMs are also important targets for current tumor immunotherapy, among which CSF1R inhibitor (PLX3397), which can block the expansion and differentiation of macrophages, has entered multiple clinical trials
.
To facilitate the clinical translation of SOX9 as a therapeutic target, the research team continued to apply LIF/LIFR inhibitors (EC359) and CSF1R inhibitors (PLX3397) to observe the effects
on tumor growth and metastasis in GAC mice.
It was found that the combination of EC359 and PLX3397 produced a better anti-tumor effect
than treatment alone, whether it was a subcutaneous implant tumor or a model of peritoneal metastasis.
The combination therapy significantly reduced peritoneal metastasis and prolonged the survival of tumor-bearing mice
.

This study is the first to report the immunosuppressive role of SOX9 gene in GAC peritoneal metastases, and elucidate that SOX9 as a cancer stem cell gene regulates the interaction between tumor cells, T cells and macrophages, thereby promoting tumor immune escape and spread metastasis
.
In summary, the study identified SOX9, a key immunosuppressive target in GAC peritoneal metastases, based on which tumor cells expressing SOX9 in the GAC microenvironment inhibited CD8 by secreting LIF T cells respond to and regulate macrophage function
.
This study revealed that SOX9 can not only be used as a target for gastric cancer cancer stem cells, but also combined targeting of LIF/LIFR and CSF1R can inhibit peritoneal metastasis of gastric adenocarcinoma, which has great value and potential
for clinical transformation.

【Reference】

1.
Clarivate CDDI database, search date: October 28, 2022.

2.
Clarivate Cortellis database, search date: October 28, 2022.

3.
Public network resources such as Medicine Cube, Academic Jingwei, Medicine Guanlan, Biovalley, Singularity Network, Medical Microphone, Translational Medicine Network, Exosome Information Network and so on.

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