Multi-target drugs for Alzheimer's disease.

Alzheimer's disease (AD), a leading cause of dementia, increasingly challenges our healthcare systems and society. Traditional therapies aimed at single targets have fallen short owing to the complex, multifactorial nature of AD that necessitates simultaneous targeting of various disease mechanisms for clinical success. Therefore, targeting multiple pathologies at the same time could provide a synergistic therapeutic effect. The identification of new disease targets beyond the classical hallmarks of AD offers a fertile ground for the design of new multi-target drugs (MTDs), and building on existing compounds have the potential to yield in successful disease modifying therapies. This review discusses the evolving landscape of MTDs, focusing on their potential as AD therapeutics. Analysis of past and current trials of compounds with multi-target activity underscores the capacity of MTDs to offer synergistic therapeutic effects, and the flourishing genetic understanding of AD will inform and inspire the development of MTD-based AD therapies.

Identification of prognostic stemness-related genes in kidney renal papillary cell carcinoma.

BACKGROUND: Kidney renal papillary cell carcinoma (KIRP) is the second most prevalent malignant cancer originating from the renal epithelium. Nowadays, cancer stem cells and stemness-related genes (SRGs) are revealed to play important roles in the carcinogenesis and metastasis of various tumors. Consequently, we aim to investigate the underlying mechanisms of SRGs in KIRP. METHODS: RNA-seq profiles of 141 KIRP samples were downloaded from the TCGA database, based on which we calculated the mRNA expression-based stemness index (mRNAsi). Next, we selected the differentially expressed genes (DEGs) between low- and high-mRNAsi groups. Then, we utilized weighted gene correlation network analysis (WGCNA) and univariate Cox analysis to identify prognostic SRGs. Afterwards, SRGs were included in the multivariate Cox regression analysis to establish a prognostic model. In addition, a regulatory network was constructed by Pearson correlation analysis, incorporating key genes, upstream transcription factors (TFs), and downstream signaling pathways. Finally, we used Connectivity map analysis to identify the potential inhibitors. RESULTS: In total, 1124 genes were characterized as DEGs between low- and high-RNAsi groups. Based on six prognostic SRGs (CCKBR, GPR50, GDNF, SPOCK3, KC877982.1, and MYO15A), a prediction model was established with an area under curve of 0.861. Furthermore, among the TFs, genes, and signaling pathways that had significant correlations, the CBX2-ASPH-Notch signaling pathway was the most significantly correlated. Finally, resveratrol might be a potential inhibitor for KIRP. CONCLUSIONS: We suggested that CBX2 could regulate ASPH through activation of the Notch signaling pathway, which might be correlated with the carcinogenesis, development, and unfavorable prognosis of KIRP.

Defeating MYC with drug combinations or dual-targeting drugs.

Members of the MYC family of proteins are a major target for cancer drug discovery, but the development of drugs that block MYC-driven cancers has not yet been successful. Approaches to achieve success may include the development of combination therapies or dual-acting drugs that target MYC at multiple nodes. Such treatments hold the possibility of additive or synergistic activity, potentially reducing side effect profiles and the emergence of resistance. In this review, we examine the prominent MYC-related targets and highlight those that have been targeted in combination and/or dual-target approaches. Finally, we explore the challenges of combination and dual-target approaches from a drug development perspective.

Potentials and future perspectives of multi-target drugs in cancer treatment: the next generation anti-cancer agents.

Cancer is a major public health problem worldwide with more than an estimated 19.3 million new cases in 2020. The occurrence rises dramatically with age, and the overall risk accumulation is combined with the tendency for cellular repair mechanisms to be less effective in older individuals. Conventional cancer treatments, such as radiotherapy, surgery, and chemotherapy, have been used for decades to combat cancer. However, the emergence of novel fields of cancer research has led to the exploration of innovative treatment approaches focused on immunotherapy, epigenetic therapy, targeted therapy, multi-omics, and also multi-target therapy. The hypothesis was based on that drugs designed to act against individual targets cannot usually battle multigenic diseases like cancer. Multi-target therapies, either in combination or sequential order, have been recommended to combat acquired and intrinsic resistance to anti-cancer treatments. Several studies focused on multi-targeting treatments due to their advantages include; overcoming clonal heterogeneity, lower risk of multi-drug resistance (MDR), decreased drug toxicity, and thereby lower side effects. In this study, we'll discuss about multi-target drugs, their benefits in improving cancer treatments, and recent advances in the field of multi-targeted drugs. Also, we will study the research that performed clinical trials using multi-target therapeutic agents for cancer treatment.

A chromatographic method for determining the interaction between a drug and two target proteins by fabricating a dual-heterogeneous surface.

Characterization of the drug-target interactions is pivotal throughout the whole procedure of drug development. Most of the current assays, particularly, chromatographic methods lack the capacity to reveal drug adsorption on the muti-target surface. To this end, we derived a reliable and workable mathematical equation for revealing drug bindings to dual targets on the heterogeneous surface starting from the mass balance equation. The derivatization relied on the correlation of drug injection amounts with their retention factors. Experimental validation was performed by determining the binding parameters of three canonical drugs on a heterogeneous surface, which was fabricated by fusing angiotensin receptor type I and type II receptors (AT1R and AT2R) at the terminuses of circularly permuted HaloTag (cpHaloTag) and immobilizing the whole fusion protein onto 6-bromohexanoic acid modified silica gel. We proved that immobilized AT1R-cpHalo-AT2R maintained the original ligand- and antibody-binding activities of the two receptors in three weeks. The association constants of valsartan, candesartan, and telmisartan to AT1R were (6.26±0.14) × 105, (9.66±0.71) × 105, and (3.17±0.03) × 105 L/mol. In the same column, their association constants to AT2R were (1.25±0.04) × 104, (2.30±0.08) × 104, and (8.51±0.06) × 103 L/mol. The patterns of the association constants to AT1R/AT2R (candesartan>valsartan>telmisartan) were in good line with the data by performing nonlinear chromatography on control columns containing immobilized AT1R or AT2R alone. This provided proof of the fact that the derivatization allowed the determination of drug bindings on the heterogeneous surface with the utilization of a single series of injections and linear regression. We reasoned that is simple enough to model the bindings of drug adsorption on commercially available adsorbents in fundamental or industrial fields, thus having the potential to become a universal method for analyzing the bindings of a drug to the heterogeneous surface containing multiple targets.

Microarray meta-analysis reveals comprehensive effects of 3,4,5-tricaffeolyquinic acid in cell differentiation and signaling.

Caffeoylquinic acids (CQA) are polyphenolic compounds found in fruits, vegetables, coffee, and spices that have exhibited several beneficial activities, including antioxidant, antibacterial, neuroprotective, anti-inflammatory, anticancer, antiviral, antidiabetic, and cardiovascular effects. A derivative, TCQA (3,4,5-Tri-O-caffeoylquinic acid), has also shown both neurogenic and pigment differentiation potential. A transcriptomic-based meta-analysis was conducted to explore potential biochemical processes and molecular targets of TCQA. This approach involved integrating data from various cell and tissue types, including human amniotic stem cells, human neural stem cells, human dermal papilla cells, and the brain cortex of aging model mice. It offered a comprehensive perspective on the significant gene regulations in response to TCQA treatment. The objective was to uncover the mechanism and novel targets of TCQA, facilitating a further understanding of its functions. New areas of interest found were TCQA's effect on adipogenesis, heart, and muscle tissue development. In addition, significantly enhanced biological activities found through meta-analysis included cell cycle, VEGFA-VEGFR2 pathway, and BMP signaling. Overall, a comprehensive functional and visual analysis using available biological databases uncovered the multi-target potential of this natural compound.

Identification of key potassium channel genes of temporal lobe epilepsy by bioinformatics analyses and experimental verification.

One of the most prevalent types of epilepsy is temporal lobe epilepsy (TLE), which has unknown etiological factors and drug resistance. The detailed mechanisms underlying potassium channels in human TLE have not yet been elucidated. Hence, this study aimed to mine potassium channel genes linked to TLE using a bioinformatic approach. The results found that Four key TLE-related potassium channel genes (TERKPCGs) were identified: potassium voltage-gated channel subfamily E member (KCNA) 1, KCNA2, potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11), and KCNS1. A protein-protein interaction (PPI) network was constructed to analyze the relationship between TERKPCGs and other key module genes. The results of gene set enrichment analysis (GSEA) for a single gene indicated that the four TERKPCGs were highly linked to the cation channel, potassium channel, respiratory chain, and oxidative phosphorylation. The mRNA-TF network was established using four mRNAs and 113 predicted transcription factors. A ceRNA network containing seven miRNAs, two mRNAs, and 244 lncRNAs was constructed based on the TERKPCGs. Three common small-molecule drugs (enflurane, promethazine, and miconazole) target KCNA1, KCNA2, and KCNS1. Ten small-molecule drugs (glimepiride, diazoxide, levosimendan, and thiamylal et al.) were retrieved for KCNJ11. Compared to normal mice, the expression of KCNA1, KCNA2, KCNJ11, and KCNS1 was downregulated in the brain tissue of the epilepsy mouse model at both the transcriptional and translational levels, which was consistent with the trend of human data from the public database. The results indicated that key potassium channel genes linked to TLE were identified based on bioinformatics analysis to investigate the potential significance of potassium channel genes in the development and treatment of TLE.

Polypharmacology: promises and new drugs in 2022.

Polypharmacology is an emerging strategy of design, synthesis, and clinical implementation of pharmaceutical agents that act on multiple targets simultaneously. It should not be mixed up with polytherapy, which is based on the use of multiple selective drugs and is considered a cornerstone of current clinical practice. However, this 'classic' approach, when facing urgent medical challenges, such as multifactorial diseases, increasing resistance to pharmacotherapy, and multimorbidity, seems to be insufficient. The 'novel' polypharmacology concept leads to a more predictable pharmacokinetic profile of multi-target-directed ligands (MTDLs), giving a chance to avoid drug-drug interactions and improve patient compliance due to the simplification of dosing regimens. Plenty of recently marketed drugs interact with multiple biological targets or disease pathways. Many offer a significant additional benefit compared to the standard treatment regimens. In this paper, we will briefly outline the genesis of polypharmacology and its differences to polytherapy. We will also present leading concepts for obtaining MTDLs. Subsequently, we will describe some successfully marketed drugs, the mechanisms of action of which are based on the interaction with multiple targets. To get an idea, of whether MTDLs are indeed important in contemporary pharmacology, we also carefully analyzed drugs approved in 2022 in Germany: 10 out of them were found multi-targeting, including 7 antitumor agents, 1 antidepressant, 1 hypnotic, and 1 drug indicated for eye disease.

Solid-Phase Parallel Synthesis of Dual Histone Deacetylase-Cyclooxygenase Inhibitors.

Multi-target drugs (MTDs) are emerging alternatives to combination therapies. Since both histone deacetylases (HDACs) and cyclooxygenase-2 (COX-2) are known to be overexpressed in several cancer types, we herein report the design, synthesis, and biological evaluation of a library of dual HDAC-COX inhibitors. The designed compounds were synthesized via an efficient parallel synthesis approach using preloaded solid-phase resins. Biological in vitro assays demonstrated that several of the synthesized compounds possess pronounced inhibitory activities against HDAC and COX isoforms. The membrane permeability and inhibition of cellular HDAC activity of selected compounds were confirmed by whole-cell HDAC inhibition assays and immunoblot experiments. The most promising dual inhibitors, C3 and C4, evoked antiproliferative effects in the low micromolar concentration range and caused a significant increase in apoptotic cells. In contrast to previous reports, the simultaneous inhibition of HDAC and COX activity by dual HDAC-COX inhibitors or combination treatments with vorinostat and celecoxib did not result in additive or synergistic anticancer activities.

Sulfated polysaccharides as multi target molecules to fight COVID 19 and comorbidities.

The majority of research to combat SARS-CoV-2 infection exploits the adaptive immune system, but innate immunity, the first line of defense against pathogenic microbes, is equally important in understanding and controlling infectious diseases. Various cellular mechanisms provide physiochemical barriers to microbe infection in mucosal membranes and epithelia, with extracellular polysaccharides, particularly sulfated polysaccharides, being among the most widespread and potent extracellular and secreted molecules blocking and deactivating bacteria, fungi, and viruses. New research reveals that a range of polysaccharides effectively inhibits COV-2 infection of mammalian cells in culture. This review provides an overview of sulfated polysaccharides nomenclature, its significance as immunomodulators, antioxidants, antitumors, anticoagulants, antibacterial, and as potent antivirals. It summarizes current research on various interactions of sulfated polysaccharide with a range of viruses, including SARS-CoV-2, and their application for potential treatments for COVID-19. These molecules interact with biochemical signaling in immune cell responses, by actions in oxidative reactions, cytokine signaling, receptor binding, and through antiviral and antibacterial toxicity. These properties provide the potential for the development of novel therapeutic treatments for SARS-CoV-2 and other infectious diseases from modified polysaccharides.

Neurotransmitters in Prevention and Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is the most frequent cause of cognitive impairment in middle-aged and older populations. There is a lack of drugs that demonstrate significant efficacy in AD, so the study of the pathogenesis of AD is of great importance. More efficacious interventions are needed, as reflected by our population's fast aging. Synaptic plasticity is the capacity of neurons to adjust their connections, and it is strongly tied to learning and memory, cognitive function, and brain injury recovery. Changes in synaptic strength, such as long-term potentiation (LTP) or inhibition (LTD), are thought to represent the biological foundation of the early stages of learning and memory. The results of numerous studies confirm that neurotransmitters and their receptors play an important role in the regulation of synaptic plasticity. However, so far, there is no definite correlation between the function of neurotransmitters in aberrant neural oscillation and AD-related cognitive impairment. We summarized the AD process to understand the impact of neurotransmitters in the progression and pathogenesis of AD, including the current status of neurotransmitter target drugs, and the latest evidence of neurotransmitters' function and changes in the AD process.

Recent advances in the molecular targeted drugs for prostate cancer.

CONTEXT: Prostate cancer (PCa) is the second largest male tumor in the world and one of the most common malignant tumors in the urinary system. In recent years, the incidence rate of PCa in China has been increasing year by year. Meanwhile, refractory hormone resistance and adverse drug reactions of advanced PCa cause serious harm to patients. OBJECTIVE: The present study aims to systematically review the recent advances in molecularly targeted drugs for prostate cancer and to use the retrieval and analysis of the literature library to summarize the adverse effects of different drugs so as to maximize the treatment benefits of targeted therapies. EVIDENCE ACQUISITION: We performed a systematic literature search of the Medline, EMBASE, PubMed, and Cochrane databases up to March 2022 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Medical Subject Heading (MeSH) terms and keywords such as (prostate cancer) AND (molecular target drugs) AND (side effect) were used. No language restrictions were set on the search process, and all these results were processed independently by two authors. Consensus was reached through discussion once met with any disagreements. The primary endpoint was differential features between different molecular targeted drugs. Secondary endpoints were side effects of different drugs on the body and corresponding prognostic values. EVIDENCE SYNTHESIS: The Cochrane Collaboration risk of bias tool was used to assess the study quality in terms of sequence generation, allocation concealment, blinding, the completeness of outcome data, selective reporting and other biases. We retrieved 332 articles, of which 49 met the criteria for inclusion. Included studies show that prostatic tumor cells, tumor neovascularization and immune checkpoints are the main means for targeted therapy. Common drugs include 177 Lu-PSMA, Olaparib, Rucaparib, Bevacizumab, Pazopanib, Sorafenib, Cabozantinib, Aflibercept, Ipilimumab, Atezolizumab, Avelumab, Durvalumab. A series of publicly available data suitable for further analysis of side effects. An over-representation analysis of these datasets revealed reasonable dosage and usage is the key to controlling the side effects of targeted drugs. Important information such as the publication year, the first author, location and outcome observation of adverse effects was extracted from the original article. If the study data has some insufficient data, contacting the corresponding authors is necessary. All the studies included prospective nonrandomized and randomized research. Retrospective reviews were also screened according to the relevant to the purpose of this study. Meeting abstracts as well as letters to the editor and editorials were excluded. STATISTICAL ANALYSIS: Data analysis was based on Cochrane's risk of bias tools to obtain the quality assessment. The included randomized studies used RoB2 and non-randomized ones corresponded to ROBINS-I. Standardized mean differences (SMD) were used to determine relative risk (RR) and side effects between groups. The eggers' test was used to check the publication bias from variable information in the included studies. All p < 0.05 were considered to be significant, and 95% was set as the confidence interval. CONCLUSIONS: With the approval of a variety of targeted drugs, targeted therapy will be widely used in the treatment of advanced or metastatic prostate cancer. Despite the existence of adverse reactions related to targeted drug treatment, it is still meaningful to adjust the drug dosage or treatment cycle to reduce the occurrence of adverse reactions, improving the treatment benefits of patients.

Docking and molecular dynamics simulation for therapeutic repurposing in small cell lung cancer (SCLC) patients infected with COVID-19.

Cancer care has become a challenge with the current COVID-19 pandemic scenario. Specially, cancers like small cell lung cancers (SCLC) are difficult to treat even in the normal situation due to their rapid growth and early metastasis. For such patients, treatment can't be compromised and care must be taken to ensure their minimum exposure to the ongoing spread of COVID-19 infection. For this reason, in-house treatments are being suggested for these patients. Another issue is that symptoms of SCLC match well with that of COVID-19 infection. Hence, the detection of COVID-19 may also get delayed leading to unnecessary complications. Thus, we have tried to investigate if the therapeutics that is currently used in lung cancer treatment can also act against SARS-CoV-2. If it is so, the same treatment protocols can be continued even if the SCLC patient had contracted COVID-19 without compromising the cancer care. For this, RNA dependent RNA polymerase (RdRP) from SARS-CoV-2 has been selected as drug target. Both docking and molecular dynamicssimulation analysis have indicated that Paclitaxel and Dacomitinib may be explored as multi-target drugs for both SCLC and COVID-19.Communicated by Ramaswamy H. Sarma.

PDT-sensitized ROS-responsive dextran nanosystem for maximizing antitumor potency of multi-target drugs.

The heterogeneity of tumor microenvironment leads to uneven distribution of bio-stimuli. Thus, the multi-site delivery efficiency of responsive drug delivery systems (DDS) inner tumor was always limited. Herein, we proposed a combination strategy of photodynamic therapy (PDT) with ROS-responsive nanosystem which was constructed from dextran-phenylboronic acid pinacol ester conjugates. This combination utilized PDT to amplify and homogenize tissular oxidation level, and achieve effective multi-site response and release of multi-target drugs like gambogic acid (GA). Our research demonstrated the successful preparation of GA and protoporphyrin IX (PpIX) co-loaded nanoparticles, and the PDT-mediated spatiotemporal controlled multi-site drug release in simulated conditions. Furthermore, data from in vitro and in vivo researches on B16F10 cells, HUVEC, and B16F10-bearing C57BL/6 mice potently confirmed the enhanced multi-mechanism regulations of GA mediated by the effective and homogeneous tumoral release. This tactic based on bio-stimuli amplification and homogenization proposes a paradigm to maximize the potency of multi-target drugs.

New Iron Metabolic Pathways and Chelation Targeting Strategies Affecting the Treatment of All Types and Stages of Cancer.

There is new and increasing evidence from in vitro, in vivo and clinical studies implicating the pivotal role of iron and associated metabolic pathways in the initiation, progression and development of cancer and in cancer metastasis. New metabolic and toxicity mechanisms and pathways, as well as genomic, transcription and other factors, have been linked to cancer and many are related to iron. Accordingly, a number of new targets for iron chelators have been identified and characterized in new anticancer strategies, in addition to the classical restriction of/reduction in iron supply, the inhibition of transferrin iron delivery, the inhibition of ribonucleotide reductase in DNA synthesis and high antioxidant potential. The new targets include the removal of excess iron from iron-laden macrophages, which affects anticancer activity; the modulation of ferroptosis; ferritin iron removal and the control of hyperferritinemia; the inhibition of hypoxia related to the role of hypoxia-inducible factor (HIF); modulation of the function of new molecular species such as STEAP4 metalloreductase and the metastasis suppressor N-MYC downstream-regulated gene-1 (NDRG1); modulation of the metabolic pathways of oxidative stress damage affecting mitochondrial function, etc. Many of these new, but also previously known associated iron metabolic pathways appear to affect all stages of cancer, as well as metastasis and drug resistance. Iron-chelating drugs and especially deferiprone (L1), has been shown in many recent studies to fulfill the role of multi-target anticancer drug linked to the above and also other iron targets, and has been proposed for phase II trials in cancer patients. In contrast, lipophilic chelators and their iron complexes are proposed for the induction of ferroptosis in some refractory or recurring tumors in drug resistance and metastasis where effective treatments are absent. There is a need to readdress cancer therapy and include therapeutic strategies targeting multifactorial processes, including the application of multi-targeting drugs involving iron chelators and iron-chelator complexes. New therapeutic protocols including drug combinations with L1 and other chelating drugs could increase anticancer activity, decrease drug resistance and metastasis, improve treatments, reduce toxicity and increase overall survival in cancer patients.

Ribosome-Directed Therapies in Cancer.

The human ribosomes are the cellular machines that participate in protein synthesis, which is deeply affected during cancer transformation by different oncoproteins and is shown to provide cancer cell proliferation and therefore biomass. Cancer diseases are associated with an increase in ribosome biogenesis and mutation of ribosomal proteins. The ribosome represents an attractive anti-cancer therapy target and several strategies are used to identify specific drugs. Here we review the role of different drugs that may decrease ribosome biogenesis and cancer cell proliferation.

Novel Rivastigmine Derivatives as Promising Multi-Target Compounds for Potential Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is the most serious and prevalent neurodegenerative disorder still without cure. Since its aetiology is diverse, recent research on anti-AD drugs has been focused on multi-target compounds. In this work, seven novel hybrids (RIV-BIM) conjugating the active moiety of the drug rivastigmine (RIV) with 2 isomeric hydroxyphenylbenzimidazole (BIM) units were developed and studied. While RIV assures the inhibition of cholinesterases, BIM provides further appropriate properties, such as inhibition of amyloid ß-peptide (Aß) aggregation, antioxidation and metal chelation. The evaluated biological properties of these hybrids included antioxidant activity; inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and Aß42 aggregation; as well as promotion of cell viability and neuroprotection. All the compounds are better inhibitors of AChE than rivastigmine (IC50 = 32.1 µM), but compounds of series 5 are better inhibitors of BChE (IC50 = 0.9-1.7 µM) than those of series 4. Series 5 also showed good capacity to inhibit self- (42.1-58.7%) and Cu(II)-induced (40.3-60.8%) Aß aggregation and also to narrow (22.4-42.6%) amyloid fibrils, the relevant compounds being 5b and 5d. Some of these compounds can also prevent the toxicity induced in SH-SY5Y cells by Aß42 and oxidative stress. Therefore, RIV-BIM hybrids seem to be potential drug candidates for AD with multi-target abilities.

Identification of Prognostic Biomarkers in Patients With Malignant Rhabdoid Tumor of the Kidney Based on mTORC1 Signaling Pathway-Related Genes.

Background: Malignant rhabdoid tumor of the kidney (MRTK) is an infrequent malignant tumor in childhood, accounting for approximately 2% of all childhood kidney tumors. Although the development of current treatments, the overall survival (OS) rate of MRTK patients is only 25%. The aim of this research was to explore the prognostic value of genes associated with the mTORC1 signaling pathway in MRTK. Methods: The transcriptome data of MRTK samples were downloaded from the TARGET database. The 200 genes of HALLMARK_MTORC1_SIGNALING were downloaded from the Molecular Signatures Database (MSigDB). Furthermore, we applied gene set variation analysis (GSVA) to screen differentially expressed gene sets between the MRTK and normal samples. The 200 genes were combined with differentially expressed genes (DEGs) identified from differentially expressed gene sets. Then, a gene signature of mTORC1 pathway-related genes (mTRGs) was constructed in MRTK. The molecular mechanism of prognostic factors in MRTK was further analyzed using gene set enrichment analysis (GSEA). The target drugs based on these prognostic factors were explored from The Comparative Toxicogenomics Database (CTD). Moreover, six paired fresh tumor tissues and paraneoplastic tissues from children with MRTK were collected to validate the expressions of P4HA1, MLLT11, AURKA, and GOT1 in clinical samples via real-time fluorescence quantitative PCR and Western blot. Results: A four-gene signature (P4HA1, MLLT11, AURKA, and GOT1) related to the mTORC1 pathway was developed in MRTK, which divided the MRTK patients into high-risk and low-risk groups. The patients with high-risk scores were strongly associated with reduced OS. Receiver operating characteristic (ROC) analysis indicated a good prediction performance of the four biomarker signatures. GSEA revealed that the mTOR signaling pathway was significantly enriched. The risk score was demonstrated to be an independent predictor for MRTK outcome. According to the correlation of tumor stem cell index and prognostic factors, the target drugs were obtained for the treatment of MRTK patients. Furthermore, the expressions of RT-qPCR and Western blot were consistent with RNA-sequencing data such that their expressions were significantly elevated in tumor tissues. Conclusion: A total of four genes (P4HA1, MLLT11, AURKA, and GOT1) were screened as prognostic markers, further providing a new understanding for the treatment of patients with MRTK.

What are the challenges with multi-targeted drug design for complex diseases?

INTRODUCTION: Current findings on multifactorial diseases with a complex pathomechanism confirm that multi-target drugs are more efficient ways in treating them as opposed to single-target drugs. However, to design multi-target ligands, a number of factors and challenges must be taken into account. AREAS COVERED: In this perspective, we summarize the concept of application of multi-target drugs for the treatment of complex diseases such as neurodegenerative diseases, schizophrenia, diabetes, and cancer. We discuss the aspects of target selection for multifunctional ligands and the application of in silico methods in their design and optimization. Furthermore, we highlight other challenges such as balancing affinities to different targets and drug-likeness of obtained compounds. Finally, we present success stories in the design of multi-target ligands for the treatment of common complex diseases. EXPERT OPINION: Despite numerous challenges resulting from the design of multi-target ligands, these efforts are worth making. Appropriate target selection, activity balancing, and ligand drug-likeness belong to key aspects in the design of ligands acting on multiple targets. It should be emphasized that in silico methods, in particular inverse docking, pharmacophore modeling, machine learning methods and approaches derived from network pharmacology are valuable tools for the design of multi-target drugs.

Efficacy of Sorafenib Combined With Immunotherapy Following Transarterial Chemoembolization for Advanced Hepatocellular Carcinoma: A Propensity Score Analysis.

Aim: The aim of the study is to compare the efficacy and safety of monotherapy with a sequential immune checkpoint inhibitor (ICI) programmed cell death protein-1 (PD-1) and its combination with multi-target drug sorafenib after transcatheter arterial chemoembolization (TACE) for advanced hepatocellular carcinoma (HCC). Methods: We conducted a retrospective evaluation of patients with advanced HCC who had received sequential PD-1 sorafenib (duplex group, n = 25) or monotherapy PD-1 alone (PD-1 group, n = 41) after TACE during April 2018-September 2021. Propensity score matching (PSM) was applied to correct the selection bias, and 22 pairs were created. The objective response rate (ORR), duration of the overall response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events were analyzed for both groups. Results: After PSM, the median PFS (7.63 vs. 2.9 months; p = 0.0335) was significantly longer for the duplex group than for the PD-1 group. The median OS (21.63 vs. 16.43 months; p = 0.103) was longer for the duplex group than for the PD-1 group, albeit without any statistical difference. The CR rate, ORR, DCR, and PFS rates at the first, third, and sixth months were higher for the duplex group than for the PD-1 group, wherein the PFS rate of the third and sixth months were statistically different. The OS rates at the sixth, 12th, and 18th months were better for the duplex group than for the PD-1 group, while the 18th-month OS rate (54.5% vs. 33.9%, p = 0.030) were statistically different between them. The most common adverse events after TACE included liver function injury, leukocytopenia, and thrombocytopenia, albeit without any statistical differences between the groups. Cox regression analysis showed that sorafenib combined immunotherapy after TACE and the achieving of CR or PR during the treatment were independent factors affecting PFS. Moreover, CNLC stage-IIIa, TACE frequency ≤2, and achievement of CR or PR were independent influencing factors of OS. Conclusions: Sequential PD-1 combined with sorafenib therapy after TACE for advanced HCC treatment is safe and effective, especially for patients with good initial treatment response, to further improve the disease prognosis.