J Biomol Struct Dyn. 2022 Feb 23:1-15. doi: 10.1080/07391102.2022.2042388. Online ahead of print.

ABSTRACT

Three receptor tyrosine kinases (RTKs), c-MET, EGFR, and VEGFR-2 have been identified as potential oncogenic targets involved in tumor development, metastasis, and invasion. Designing inhibitors that can simultaneously interact with multiple targets is a promising approach, therefore, inhibiting these three RTKs with a single chemical component might give an effective chemotherapeutic strategy for addressing the disease while limiting adverse effects. The in-silico methods have been developed to identify the polypharmacological inhibitors particularly for drug repurposing and multitarget drug design. Here, to find a viable inhibitor from natural source against these three RTKs, structure-based pharmacophore mapping and virtual screening of SN-II database were carried out. The filtered compound SN00020821, identified as Cedeodarin, from different computational approaches, demonstrated good interactions with all the three targets, c-MET/EGFR/VEGFR-2, with interaction energies of -42.35 kcal/mol, -49.32 kcal/mol and -44.83 kcal/mol, respectively. SN00020821displayed stable key interactions with critical amino acids of all the three receptors' kinase catalytic domains including "DFG motif" explored through the MD simulations. Furthermore, it also met the ADMET requirements and was determined to be drug-like as predicted from the Lipinski's rule of five and Veber's rule. Finally, SN00020821 provides a novel molecular scaffold that could be investigated further as a polypharmacological anticancer therapeutic candidate that targets the three RTKs.Communicated by Ramaswamy H. Sarma.

PMID:35196966 | DOI:10.1080/07391102.2022.2042388

Mol Inform. 2022 Feb 23. doi: 10.1002/minf.202100300. Online ahead of print.

ABSTRACT

The present study focuses on the interconnected functional network of altered metabolism and EMT (epithelial to mesenchymal transition) signaling in breast cancer. We have interlinked the metabolic and EMT signaling circuits and selected Insulin receptor (IR), Integrin beta 1 (ITGB1), and CD36 as target proteins based on network analysis. Extensive computational approaches discerned the potential drug molecules from the library of 1293 FDA-approved drugs to block all three target proteins. Using molecular docking, molecular dynamics simulation, and MMPBSA binding free energy studies, Capmatinib, Ponatinib, Naldemedine, and Pimozide were identified as potential repurposed drugs to block the function of all three target proteins. Among in silico selected candidate drugs, Pimozide, a known anti-psychotic drug, was further validated using in-vitro studies for its anti-cell proliferative potential on breast cancer cell lines (namely, MCF7, MDAMB231 and MDAMB468). The inhibitory concentration (IC50) values of MCF7, MDAMB231 and MDAMB468 was found to be 16.26 µM, 20.82 µM and 13.10 µM, respectively. The effect of Pimozide on EMT-induced MDAMB231 and MDAMB468 cells was evident from their IC50 values of 7.85 µM and 6.83 µM, respectively. The potent anti-cancer property of Pimozide has opened up avenues for drug repurposing towards 'multi-targeted therapy' in EMT dynamics.

PMID:35195941 | DOI:10.1002/minf.202100300

bioRxiv. 2022 Feb 18:2022.02.17.480940. doi: 10.1101/2022.02.17.480940. Preprint.

ABSTRACT

BACKGROUND: Despite a great deal of interest in the application of artificial intelligence (AI) to sepsis/critical illness, most current approaches are limited in their potential impact: prediction models do not (and cannot) address the lack of effective therapeutics and current approaches to enhancing the treatment of sepsis focus on optimizing the application of existing interventions, and thus cannot address the development of new treatment options/modalities. The inability to test new therapeutic applications was highlighted by the generally unsatisfactory results from drug repurposing efforts in COVID-19.

HYPOTHESIS: Addressing this challenge requires the application of simulation-based, model-free deep reinforcement learning (DRL) in a fashion akin to training the game-playing AIs. We have previously demonstrated the potential of this method in the context of bacterial sepsis in which the microbial infection is responsive to antibiotic therapy. The current work addresses the control problem of multi-modal, adaptive immunomodulation in the circumstance where there is no effective anti-pathogen therapy (e.g., in a novel viral pandemic or in the face of resistant microbes).

METHODS: This is a proof-of-concept study that determines the controllability of sepsis without the ability to pharmacologically suppress the pathogen. We use as a surrogate system a previously validated agent-based model, the Innate Immune Response Agent-based Model (IIRABM), for control discovery using DRL. The DRL algorithm 'trains' an AI on simulations of infection where both the control and observation spaces are limited to operating upon the defined immune mediators included in the IIRABM (a total of 11). Policies were learned using the Deep Deterministic Policy Gradient approach, with the objective function being a return to baseline system health.

RESULTS: DRL trained an AI policy that improved system mortality from 85% to 10.4%. Control actions affected every one of the 11 targetable cytokines and could be divided into those with static/unchanging controls and those with variable/adaptive controls. Adaptive controls primarily targeted 3 different aspects of the immune response: 2 nd order pro-inflammation governing TH1/TH2 balance, primary anti-inflammation, and inflammatory cell proliferation.

DISCUSSION: The current treatment of sepsis is hampered by limitations in therapeutic options able to affect the biology of sepsis. This is heightened in circumstances where no effective antimicrobials exist, as was the case for COVID-19. Current AI methods are intrinsically unable to address this problem; doing so requires training AIs in contexts that fully represent the counterfactual space of potential treatments. The synthetic data needed for this task is only possible through the use of high-resolution, mechanism-based simulations. Finally, being able to treat sepsis will require a reorientation as to the sensing and actuating requirements needed to develop these simulations and bring them to the bedside.

PMID:35194613 | PMC:PMC8863155 | DOI:10.1101/2022.02.17.480940

STAR Protoc. 2022 Jan 24;3(1):101158. doi: 10.1016/j.xpro.2022.101158. eCollection 2022 Mar 18.

ABSTRACT

The SARS-CoV-2 main protease of (Mpro) is an important target for SARS-CoV-2 related drug repurposing and development studies. Here, we describe the steps for structural characterization of SARS-CoV-2 Mpro, starting from plasmid preparation and protein purification. We detail the steps for crystallization using the sitting drop, microbatch (under oil) approach. Finally, we cover data collection and structure determination using serial femtosecond crystallography. For complete details on the use and execution of this protocol, please refer to Durdagi et al. (2021).

PMID:35194584 | PMC:PMC8784426 | DOI:10.1016/j.xpro.2022.101158

Drug Discov Today. 2022 Feb 19:S1359-6446(22)00071-X. doi: 10.1016/j.drudis.2022.02.012. Online ahead of print.

ABSTRACT

The clinical, social, and economic impacts of the coronavirus disease 2019 (COVID-19) pandemic, originated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have motivated a massive search and investment to find treatments for this new disease. Repurposing drugs has been an appealing strategy for the rapid translation of in vitro and ex vivo drug discovery to the clinic. Several repurposed drugs have been assessed clinically, but no effective repurposed antiviral has been identified so far. Of note, no effective treatments for COVID-19 or for any other viral disease have been found by repurposing drugs identified through hypothesis-free screens. Here, I discuss whether drug repurposing is the best strategy for developing effective therapies to eradicate COVID-19 and other viral human infections.

PMID:35192924 | DOI:10.1016/j.drudis.2022.02.012

Elife. 2022 Feb 22;11:e71880. doi: 10.7554/eLife.71880. Online ahead of print.

ABSTRACT

Pharmacologic perturbation projects, such as Connectivity Map (CMap) and Library of Integrated Network-based Cellular Signatures (LINCS), have produced many perturbed expression data, providing enormous opportunities for computational therapeutic discovery. However, there is no consensus on which methodologies and parameters are the most optimal to conduct such analysis. Aiming to fill this gap, new benchmarking standards were developed to quantitatively evaluate drug retrieval performance. Investigations of potential factors influencing drug retrieval were conducted based on these standards. As a result, we determined an optimal approach for LINCS data-based therapeutic discovery. With this approach, homoharringtonine (HHT) was identified to be a candidate agent with potential therapeutic and preventive effects on liver cancer. The antitumor and antifibrotic activity of HHT was validated experimentally using subcutaneous xenograft tumor model and carbon tetrachloride (CCL4)-induced liver fibrosis model, demonstrating the reliability of the prediction results. In summary, our findings will not only impact the future applications of LINCS data but also offer new opportunities for therapeutic intervention of liver cancer.

PMID:35191375 | DOI:10.7554/eLife.71880

Phytomedicine. 2022 Feb 12;99:153984. doi: 10.1016/j.phymed.2022.153984. Online ahead of print.

ABSTRACT

BACKGROUND: Immunomodulatory drugs are currently used for immunosuppressed individuals, but adverse side effects have been reported. Although Panax ginseng and Scrophularia buergeriana are known to have respective pharmacological properties, the potential of a mixture of Panax ginseng and Scrophularia buergeriana (Isam-Tang, IST) as an immunomodulatory drug has not yet been studied.

PURPOSE: The present study was designed to assess the immunomodulatory activity of IST and p-coumaric acid (pCA), an active compound of IST, in the immune system.

METHODS: The levels of immunostimulatory cytokines, nitrite, inducible nitric oxide synthase (iNOS), NF-kB activation, and proliferation were examined in RAW264.7 cells, primary splenocytes and splenic NK cells isolated from normal mouse spleen, and in cyclophosphamide-induced immunosuppressed mice using ELISA, quantitative real-time PCR, Western blotting, and immunofluorescence staining.

RESULTS: IST or pCA treatment increased the production of immunostimulatory cytokines and nitrite and the expression of iNOS in RAW264.7 cells and splenocytes. IST or pCA also induced NF-κB signaling activation and promoted the phagocytic activity of RAW264.7 cells. In addition, the splenocyte proliferation and splenic NK activity were enhanced by IST or pCA. IST or pCA increased the levels of immunostimulatory cytokines in immunosuppressed mice and ameliorated splenic tissue damage.

CONCLUSION: These findings suggest that IST supplementation may be used to enhance immune function.

PMID:35189478 | DOI:10.1016/j.phymed.2022.153984

Microb Pathog. 2022 Feb 18:105454. doi: 10.1016/j.micpath.2022.105454. Online ahead of print.

ABSTRACT

Gonococcal infections represent an urgent public health threat worldwide due to the increasing incidence of infections that has been accompanied by an increase in bacterial resistance to most antibiotics. This has resulted in a dwindling number of effective treatment options. Undoubtedly, there is a critical need to develop new, effective anti-gonococcal agents. In an effort to discover new anti-gonococcal therapeutics, we previously identified acetazolamide, a carbonic anhydrase inhibitor, as a novel inhibitor of Neisseria gonorrhoeae. Acetazolamide exhibited potent anti-gonococcal activity in vitro as it inhibited growth of strains of N. gonorrhoeae at concentrations that ranged from 0.5 to 4 μg/mL. The aim of this study was to investigate the in vivo efficacy of acetazolamide in a mouse model of N. gonorrhoeae genital tract infection. Compared to vehicle-treated mice, acetazolamide significantly reduced the gonococcal burden by 90% in the vagina of infected mice after three days of treatment. These results indicate that acetazolamide warrants further investigation as a promising treatment option to supplement the limited pipeline of anti-gonococcal therapeutics.

PMID:35189278 | DOI:10.1016/j.micpath.2022.105454

Immunotherapy. 2022 Feb 21. doi: 10.2217/imt-2021-0168. Online ahead of print.

ABSTRACT

The COVID-19 pandemic is a lethal virus outbreak by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which has severely affected human lives and the global economy. The most vital part of the research and development of therapeutic agents is to design drug products to manage COVID-19 efficiently. Numerous attempts have been in place to determine the optimal drug dose and combination of drugs to treat the disease on a global scale. This article documents the information available on SARS-CoV-2 and its life cycle, which will aid in the development of the potential treatment options. A consolidated summary of several natural and repurposed drugs to manage COVID-19 is depicted with summary of current vaccine development. People with high age, comorbity and concomitant illnesses such as overweight, metabolic disorders, pulmonary disease, coronary heart disease, renal failure, fatty liver and neoplastic disorders are more prone to create serious COVID-19 and its consequences. This article also presents an overview of post-COVID-19 complications in patients.

PMID:35187954 | DOI:10.2217/imt-2021-0168

Cell Genom. 2022 Feb;2(2):100095. doi: 10.1016/j.xgen.2022.100095.

ABSTRACT

Pancreatic cancer (PDAC) is a highly aggressive malignancy for which the identification of novel therapies is urgently needed. Here, we establish a human PDAC organoid biobank from 31 genetically distinct lines, covering a representative range of tumor subtypes, and demonstrate that these reflect the molecular and phenotypic heterogeneity of primary PDAC tissue. We use CRISPR-Cas9 genome editing and drug screening to characterize drug-gene interactions with ARID1A and BRCA2. We find that missense- but not frameshift mutations in the PDAC driver gene ARID1A are associated with increased sensitivity to the kinase inhibitors dasatinib (p < 0.0001) and VE-821 (p < 0.0001). We conduct an automated drug-repurposing screen with 1,172 FDA-approved compounds, identifying 26 compounds that effectively kill PDAC organoids, including 19 chemotherapy drugs currently approved for other cancer types. We validate the activity of these compounds in vitro and in vivo. The in vivo validated hits include emetine and ouabain, compounds which are approved for non-cancer indications and which perturb the ability of PDAC organoids to respond to hypoxia. Our study provides proof-of-concept for advancing precision oncology and identifying candidates for drug repurposing via genome editing and drug screening in tumor organoid biobanks.

PMID:35187519 | PMC:PMC7612395 | DOI:10.1016/j.xgen.2022.100095

Front Oncol. 2022 Feb 3;12:836882. doi: 10.3389/fonc.2022.836882. eCollection 2022.

ABSTRACT

Despite the significant progress in cancer treatment, new anticancer therapeutics drugs with new structures and/or mechanisms are still in urgent need to tackle many key challenges. Drug repurposing is a feasible strategy in discovering new drugs among the approved drugs by defining new indications. Recently, ropivacaine, a local anesthetic that has been applied in clinical practice for several decades, has been found to possess inhibitory activity and sensitizing effects when combined with conventional chemotherapeutics toward cancer cells. While its full applications and the exact targets remain to be revealed, it has been indicated that its anticancer potency was mediated by multiple mechanisms, such as modulating sodium channel, inducing mitochondria-associated apoptosis, cell cycle arrest, inhibiting autophagy, and/or regulating other key players in cancer cells, which can be termed as multi-targets/functions that require more in-depth studies. In this review, we attempted to summarize the research past decade of using ropivacaine in suppressing cancer growth and sensitizing anticancer drugs both in-vitro and in-vivo, and tried to interpret the underlying action modes. The information gained in these findings may inspire multidisciplinary efforts to develop/discover more novel anticancer agents via drug repurposing.

PMID:35186766 | PMC:PMC8851418 | DOI:10.3389/fonc.2022.836882

Front Oncol. 2022 Feb 2;12:809014. doi: 10.3389/fonc.2022.809014. eCollection 2022.

ABSTRACT

BACKGROUND: Although several epigenetic drugs have been reported to have therapeutic efficacy for some hematologic neoplasms (HNs) in clinical trials, few achieved disease-free survival benefit. The traditional drug discovery pathway is costly and time-consuming, and thus, more effective strategies are required. We attempted to facilitate epigenetic drug repositioning for therapy of HNs by screening the Human Epigenetic Drug Database (HEDD) in the web, conducting a bench-work cytotoxicity test and a retrospective nationwide cohort study prior to a clinical trial.

METHODS: Four FDA-approved epigenetic drugs with antitumor properties and completion of clinical phase II trials were selected from HEDD. Hydralazine (HDZ) and valproate (VAL) among the four were selected with higher cytotoxicity to HN cells, no matter whether carrying the JAK2V617F mutation or not. Both of them were chosen for a cohort study using the Longitudinal Health Insurance Database (LHID) 2000-2015 (N = 1,936,512), a subset of the National Health Insurance Research Database (NHIRD, N= 25.68 millions) in Taiwan.

RESULTS: In the initial cohort, HDZ or VAL exposure subjects (11,049) and matching reference subjects (44,196) were enrolled according to maximal daily consumption (300/2,100 mg per day of HDZ/VAL). The HN incidence in HDZ and VAL exposure groups reduced from 4.97% to 3.90% (p <.001) and 4.45% (p = .075), respectively. A further cohort study on HDZ at a lower range of the WHO defined daily dose (<34 mg per day) and HN incidence of HDZ exposure subjects (75,612) reduced from 5.01% to 4.16% (p = 1.725 × 10 -18) compared to the reference subjects (302,448).

CONCLUSIONS: An association of a chronically prescribed HDZ, even prescribed low dose, with reduction of overall incidence rate and in most subgroups of HN was observed in our study. Repositioning HDZ for HN management may be feasible. This is the first nationwide cohort study of the epigenetics-associated risk evaluation of overall HN in the existing literature, showing an effective method with a wider scope to inform contemporary clinical trials of epigenetic drugs in the future.

PMID:35186746 | PMC:PMC8848747 | DOI:10.3389/fonc.2022.809014

Front Microbiol. 2022 Feb 4;12:783284. doi: 10.3389/fmicb.2021.783284. eCollection 2021.

ABSTRACT

A majority of microbial infections are associated with biofilms. Targeting biofilms is considered an effective strategy to limit microbial virulence while minimizing the development of antibiotic resistance. Toward this need, antibiofilm peptides are an attractive arsenal since they are bestowed with properties orthogonal to small molecule drugs. In this work, we developed machine learning models to identify the distinguishing characteristics of known antibiofilm peptides, and to mine peptide databases from diverse habitats to classify new peptides with potential antibiofilm activities. Additionally, we used the reported minimum inhibitory/eradication concentration (MBIC/MBEC) of the antibiofilm peptides to create a regression model on top of the classification model to predict the effectiveness of new antibiofilm peptides. We used a positive dataset containing 242 antibiofilm peptides, and a negative dataset which, unlike previous datasets, contains peptides that are likely to promote biofilm formation. Our model achieved a classification accuracy greater than 98% and harmonic mean of precision-recall (F1) and Matthews correlation coefficient (MCC) scores greater than 0.90; the regression model achieved an MCC score greater than 0.81. We utilized our classification-regression pipeline to evaluate 135,015 peptides from diverse sources for potential antibiofilm activity, and we identified 185 candidates that are likely to be effective against preformed biofilms at micromolar concentrations. Structural analysis of the top 37 hits revealed a larger distribution of helices and coils than sheets, and common functional motifs. Sequence alignment of these hits with known antibiofilm peptides revealed that, while some of the hits showed relatively high sequence similarity with known peptides, some others did not indicate the presence of antibiofilm activity in novel sources or sequences. Further, some of the hits had previously recognized therapeutic properties or host defense traits suggestive of drug repurposing applications. Taken together, this work demonstrates a new in silico approach to predicting antibiofilm efficacy, and identifies promising new candidates for biofilm eradication.

PMID:35185814 | PMC:PMC8856603 | DOI:10.3389/fmicb.2021.783284

BMC Bioinformatics. 2022 Feb 19;23(1):76. doi: 10.1186/s12859-022-04590-5.

ABSTRACT

BACKGROUND: PubMed contains millions of abstracts that co-mention terms that describe drugs with other biomedical terms such as genes or diseases. Unique opportunities exist for leveraging these co-mentions by integrating them with other drug-drug similarity resources such as the Library of Integrated Network-based Cellular Signatures (LINCS) L1000 signatures to develop novel hypotheses.

RESULTS: DrugShot is a web-based server application and an Appyter that enables users to enter any biomedical search term into a simple input form to receive ranked lists of drugs and other small molecules based on their relevance to the search term. To produce ranked lists of small molecules, DrugShot cross-references returned PubMed identifiers (PMIDs) with DrugRIF or AutoRIF, which are curated resources of drug-PMID associations, to produce an associated small molecule list where each small molecule is ranked according to total co-mentions with the search term from shared PubMed IDs. Additionally, using two types of drug-drug similarity matrices, lists of small molecules are predicted to be associated with the search term. Such predictions are based on literature co-mentions and signature similarity from LINCS L1000 drug-induced gene expression profiles.

CONCLUSIONS: DrugShot prioritizes drugs and small molecules associated with biomedical search terms. In addition to listing known associations, DrugShot predicts additional drugs and small molecules related to any search term. Hence, DrugShot can be used to prioritize drugs and preclinical compounds for drug repurposing and suggest indications and adverse events for preclinical compounds. DrugShot is freely and openly available at: https://maayanlab.cloud/drugshot and https://appyters.maayanlab.cloud/#/DrugShot .

PMID:35183110 | DOI:10.1186/s12859-022-04590-5

Drug Discov Today. 2022 Feb 16:S1359-6446(22)00064-2. doi: 10.1016/j.drudis.2022.02.007. Online ahead of print.

ABSTRACT

Given the substantial cost and low success rate of drug discovery and development, repositioning existing drugs to treat new diseases has gained significant attention in recent years, with potentially lower development costs and shorter time frames. Natural products show great promise in drug repositioning because they have been used for various medical purposes for thousands of years. In this review, we discuss the drug repositioning of six prototypical natural products and their derivatives to reveal new drug-disease associations. We also highlight opportunities and challenges in natural product-based drug repositioning for future reference.

PMID:35182736 | DOI:10.1016/j.drudis.2022.02.007

Drug Discov Today. 2022 Feb 16:S1359-6446(22)00065-4. doi: 10.1016/j.drudis.2022.02.008. Online ahead of print.

ABSTRACT

Here, we propose a broad concept of 'Clinical Outcome Pathways' (COPs), which are defined as a series of key molecular and cellular events that underlie therapeutic effects of drug molecules. We formalize COPs as a chain of the following events: molecular initiating event (MIE) → intermediate event(s) → clinical outcome. We illustrate the concept with COP examples both for primary and alternative (i.e., drug repurposing) therapeutic applications. We also describe the elucidation of COPs for several drugs of interest using the publicly accessible Reasoning Over Biomedical Objects linked in Knowledge-Oriented Pathways (ROBOKOP) biomedical knowledge graph-mining tool. We propose that broader use of COP uncovered with the help of biomedical knowledge graph mining will likely accelerate drug discovery and repurposing efforts.

PMID:35182735 | DOI:10.1016/j.drudis.2022.02.008

J Biomed Nanotechnol. 2022 Jan 1;18(1):97-111. doi: 10.1166/jbn.2022.3217.

ABSTRACT

Itraconazole (ITC), an antifungal drug with anticancer activity, shows potential for oral treatment of skin cancer. There is clinical need for topical ITC for treating low-risk skin carcinogenesis. Our objective was to develop ITC nanoformulations with enhanced anticancer efficacy. Lipid nanocapsules (LNC), either unmodified (ITC/LNC) or modified with the amphiphiles miltefosine (ITC/MF-LNC) or the lipopeptide biosurfactant surfactin (ITC/SF-LNC) as bioactive additives were developed. LNC formulations showed high ITC entrapment efficiency (>98%), small diameter (42-45 nm) and sustained ITC release. Cytotoxicity studies using malignant SCC 9 cells and normal human fibroblasts (NHF) demonstrated significant enhancement of ITC anticancer activity and selectivity for cancer cells by the LNC formulations and a synergistic ITC-amphiphile interaction improving the combination performance. Treatment of intradermal tumor-bearing mice with the ITC nanoformulation gels compared with ITC and 5-FU gels achieved significant tumor growth inhibition that was remarkably enhanced by ITC/MF-LNC and ITC/SF-LNC as well as recovery of skin architecture. Molecularly, tumoral expression of Ki-67 and cytokeratin proliferative proteins was significantly suppressed by LNC formulations, the suppressive effect on cytokeratins was superior to that of 5-FU. These findings provide new evidence for effective topical treatment of low-risk skin carcinogenesis utilizing multiple approaches that involve drug repurposing, nanotechnology, and bioactive amphiphiles as formulation enhancing additives.

PMID:35180903 | DOI:10.1166/jbn.2022.3217

Expert Opin Drug Discov. 2022 Feb 18:1-12. doi: 10.1080/17460441.2022.2039619. Online ahead of print.

ABSTRACT

INTRODUCTION: Triple-negative breast cancer (TNBC) is of great concern due to its aggressiveness and lack of targeted therapy. For these reasons, TNBC is one of the main causes of death in women, mainly due to metastases. Tumor dissemination has highlighted a set of possible targets, with extensive research into new single-target drugs, in addition to drug repurposing strategies, being undertaken to discover new classes of potential inhibitors of metastasis.

AREAS COVERED: The authors here describe the main proposed targets and the bases of their pharmacological inhibition with different chemical compounds. The authors also discuss the state-of-the-art from the latest clinical trials and highlight other potential targets for metastatic TNBC.

EXPERT OPINION: In the last decade, oncology research has changed its focus from primary tumors to moving tumor cells, their products, and to the secondary tumor and its surroundings, for the purpose of finding targets to treat metastasis. Consequently, our comprehension of the complexity of the metastatic process has increased drastically, with, furthermore, the discovery of new potential targets. Although promising, the wide range of strategies is still not effective to suppress TNBC metastasis in terms of increasing patient survival or decreasing the number of metastases. Treating or preventing metastasis continues to be a great challenge.

PMID:35179448 | DOI:10.1080/17460441.2022.2039619

Clin Cancer Drugs. 2021 Mar;8(1):50-56. doi: 10.2174/2212697x08666210219101023. Epub 2021 Feb 19.

ABSTRACT

BACKGROUND: Breast cancer is the most frequently diagnosed cancer in women worldwide. Pyronaridine (PND), an antimalarial drug, was shown to exert anticancer activity on seventeen different human cancer cells, seven from female breast tissue. Additionally, PND induced apoptosis via mitochondrial depolarization, alteration of cell cycle progression, and DNA intercalation. However, the molecular target of PND in cells was not elucidated.

OBJECTIVE: Here, we have further investigated PND's mode of action by using transcriptome analysis. Preclinical studies were also performed to determine whether PND could affect tumor progression in a human breast cancer xenograft in mice. Moreover, we assessed the combined efficacy of PND with well-known anticancer drugs.

METHODS: Transcriptome analyses of PND-treated cancer cells were performed. Topoisomerase II activity was evaluated by an in vitro assay. In addition, daily oral administration of PND was given to mice with human breast cancer xenografts. The differential nuclear staining assay measured in-vitro cell toxicity.

RESULTS: The transcriptome signatures suggested that PND might act as a topoisomerase II inhibitor. Thus, topoisomerase inhibition assays were performed, providing evidence that PND is a bona fide topoisomerase II inhibitor. Also, in-vivo studies suggest that PND hinders tumor progression. Besides, combination studies of PND with anticancer drugs cisplatin and gemcitabine revealed higher cytotoxicity against cancer cells than individual drug administration.

CONCLUSION: The findings provide evidence that PND is a topoisomerase II inhibitor and can hinder cancer progression in an animal model, further demonstrating PND's favorable characteristics as a repurposed anticancer drug.

PMID:35178342 | PMC:PMC8849572 | DOI:10.2174/2212697x08666210219101023

J Med Chem. 2022 Feb 17. doi: 10.1021/acs.jmedchem.1c01993. Online ahead of print.

ABSTRACT

Our previous work found that the clinical histone deacetylase (HDAC) inhibitor quisinostat exhibited a significant antimalarial effect but with severe toxicity. In this work, 35 novel derivatives were designed and synthesized based on quisinostat as the lead compound, and their in vitro antimalarial activities and cytotoxicities were systematically evaluated. Among them, JX35 showed potent inhibition against both wild-type and multidrug-resistant parasite strains and displayed a significant in vivo killing effect against all life cycles of parasites, including the blood stage, liver stage, and gametocyte stage, indicating its potential for the simultaneous treatment, chemoprevention, and blockage of malaria transmission. Compared with quisinostat, JX35 exhibited stronger antimalarial efficacy, more adequate safety, and good pharmacokinetic properties. Additionally, mechanistic studies via molecular docking studies, induced PfHDAC1/2 knockdown assays, and PfHDAC1 enzyme inhibition assays jointly indicated that the antimalarial target of JX35 was PfHDAC1. In summary, we discovered the promising candidate PfHDAC1 inhibitor JX35, which showed stronger triple-stage antimalarial effects and lower toxicity than quisinostat.

PMID:35175762 | DOI:10.1021/acs.jmedchem.1c01993