Drug Development Research最新文献

{"title":"Does Metabolic Manager Show Encouraging Outcomes in Alzheimer's?: Challenges and Opportunity for Protein Tyrosine Phosphatase 1b Inhibitors","authors":"Ritu Singh,&nbsp;Smita Jain,&nbsp;Vartika Paliwal,&nbsp;Kanika Verma,&nbsp;Sarvesh Paliwal,&nbsp;Swapnil Sharma","doi":"10.1002/ddr.70026","DOIUrl":"10.1002/ddr.70026","url":null,"abstract":"<div>\u0000 \u0000 <p>Protein tyrosine phosphatase 1b (PTP1b) is a member of the protein tyrosine phosphatase (PTP) enzyme group and encoded as <i>PTP1N</i> gene. Studies have evidenced an overexpression of the PTP1b enzyme in metabolic syndrome, anxiety, schizophrenia, neurodegeneration, and neuroinflammation. PTP1b inhibitor negatively regulates insulin and leptin pathways and has been explored as an antidiabetic agent in various clinical trials. Notably, the preclinical studies have shown that recuperating metabolic dysfunction and dyshomeostasis can reverse cognition and could be a possible approach to mitigate multifaceted Alzheimer's disease (AD). PTP1b inhibitor thus has attracted attention in neuroscience, though the development is limited to the preclinical stage, and its exploration in large clinical trials is warranted. This review provides an insight on the development of PTP1b inhibitors from different sources in diabesity. The crosstalk between metabolic dysfunction and insulin insensitivity in AD and type-2 diabetes has also been highlighted. Furthermore, this review presents the significance of PTP1b inhibition in AD based on pathophysiological facets, and recent evidences from preclinical and clinical studies.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 8","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anxiolytic Effect of Sesamol, Possibly Through the GABAkine Interaction Pathway","authors":"Md. Tahajul Islam,&nbsp;Abdul Malik,&nbsp;Abdullah K. Alshememry,&nbsp;Raihan Chowdhury,&nbsp;Md. Shimul Bhuia,&nbsp;Sabiha Fatima,&nbsp;Md. Samim Hossen,&nbsp;Asraful Islam Rakib,&nbsp;Faysal Mollah,&nbsp;Md. Showkoth Akbor,&nbsp;Mehedi Hasan Bappi,&nbsp;Md. Abu Saim,&nbsp;Muhammad Torequl Islam","doi":"10.1002/ddr.70028","DOIUrl":"10.1002/ddr.70028","url":null,"abstract":"<div>\u0000 \u0000 <p>Plant-based components have helped generate novel lead molecules and scaffolds for anxiety research in psychopharmacology. The present study examined the anxiolytic properties of sesamol (SES), a phenolic lignan derived from <i>Sesamum indicum</i>, employing both in vivo and computational methods to understand its mechanisms of action. In this experiment, adult <i>Swiss</i> albino mice received various doses of SES (25 and 50 mg/kg, p.o.) orally. Afterward, a series of behavioral assessments, including open field, swing, hole cross, and light–dark testing, were conducted. The impact of the GABAergic agonist diazepam (DZP-1 mg/kg, i.p.) along with the antagonist flumazenil (FLU-0.1 mg/kg, i.p.) has been studied as provided concurrently with the SES-50 group. Computational studies were performed to comprehend the interaction between SES and GABA_A receptor subunits (α₂ and α₃). The results of our investigation revealed that SES dose-dependently and significantly (<i>p</i> &lt; 0.05) reduced the number of square crosses, hole crosses, swings, grooming, and rearing along with a reduction of light residence time in animals. When combined with DZP, SES-50 significantly reduced all these parameters, while altering with FLU-0.1. The molecular docking analysis showed that the SES has a relatively good binding score (−5.03 ± 0.15 and −5.25 ± 0.23 kcal/mol) with GABA_A receptor α₂ and α₃ subunits, respectively. The SES triggers anxiolytic effects via GABA_A receptor α₂ and α₃ subunit interactions. Furthermore, precise and comprehensive preclinical research must be considered to validate potential SES targets for anxiolytic impact, clinical trial efficacy, and safety.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 8","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improving the Biopharmaceutical Properties of Cannabinoids in Glioblastoma Multiforme Therapy With Nanotechnology: A Drug Delivery Perspective","authors":"Stephanie B. Walker,&nbsp;Jonatas L. Duarte,&nbsp;Leonardo D. Di Filippo,&nbsp;Marlus Chorilli","doi":"10.1002/ddr.70023","DOIUrl":"https://doi.org/10.1002/ddr.70023","url":null,"abstract":"<div>\u0000 \u0000 <p>Glioblastoma multiforme (GBM) is the most prevalent primary brain tumor in adults and is known for its rapid proliferation and infiltrative nature. Current therapeutic strategies include surgical resection followed by radio- and chemotherapy. Still, they are hindered by GBM biological characteristics and physical-chemical properties of chemotherapeutic drugs, leading to limited efficacy and poor prognosis. Cannabinoids have emerged as potential anti-GBM agents, exhibiting antiangiogenic, antimetastatic, and antiproliferative effects. However, their hydrophobicity and poor oral bioavailability pose significant challenges for clinical applications. This study evaluates the potential of nanocarriers in enhancing the solubility and targeted delivery of cannabinoids for GBM therapy. The innovative combination of nanotechnology with cannabinoid-based treatment offers a promising strategy to improve therapeutic outcomes. We addressed the application of nanocarriers to deliver cannabinoids, which can enhance passage across the blood-brain barrier and enable targeted therapy. Studies demonstrate the potential of nanocarriers in improving solubility, stability, and controlled release of cannabinoids, highlighting the advancements in nanocarrier design for optimized delivery to glioma cells. Cannabinoids can exert their antitumor effect, including the induction of apoptosis through the ceramide and p8-regulated pathways and the modulation of immune responses. The evidence found in this study supports the potential of cannabinoid-based nanotechnologies in GBM therapeutic regimens as a strategy to enhance its efficacy and patient outcomes.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 8","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142762519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New Dichalcogenides Induce Oxidative Stress and Cell Death of Leishmania amazonensis","authors":"Andressa Dalólio Valente,&nbsp;Rian Richard Santos de Farias,&nbsp;Tay Takeshita Botogoske Zugman,&nbsp;Leandro Piovan,&nbsp;Celso Vataru Nakamura,&nbsp;Francielle Pelegrin Garcia","doi":"10.1002/ddr.70018","DOIUrl":"10.1002/ddr.70018","url":null,"abstract":"<div>\u0000 \u0000 <p>Leishmaniasis are caused by protozoa of the genus <i>Leishmania</i> and affect millions of people worldwide. They are considered neglected diseases that primarily impact individuals in tropical and subtropical regions. The drugs currently available for treating this infection have limitations, such as high toxicity, adverse reactions, and a long therapeutic intervention period. Numerous studies, using various experimental models, have sought to develop more effective and less toxic chemotherapeutic agents against these protozoa. In this context, the present study aimed to evaluate the antileishmanial activity of two new dichalcogenides, LQ64 and LQ62, as well as their possible mechanism of action in promastigote forms of <i>Leishmania amazonensis</i>. Both substances, LQ64 and LQ62, exhibited activity against promastigote (IC₅₀ = 2.35 and 12.59 µM, respectively), and amastigote forms (IC₅₀ = 3.50 and 6.58 µM, respectively). Furthermore, the substances revealed selectivity for the parasite when analyzing their cytotoxicity in J774A-1 macrophages. Moreover, electron microscopy analysis and mechanisms of action assays investigated in promastigote forms with both substances showed mitochondrial depolarization. This phenomenon possibly promoted changes in intracellular ATP levels, resulting in increased reactive species and lipid peroxidation, leading the parasites to oxidative stress. Additionally, the treatments induced changes in plasma membrane integrity, lipid body accumulation, alterations in the cell cycle, and phosphatidylserine externalization. Thus, the results indicate that LQ64 and LQ62 may induce characteristic changes in the protozoan suggestive of apoptosis cell death.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 8","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, Synthesis, and Biological Activities Evaluation of Type I FLT3 Inhibitors for the Treatment of Acute Myeloid Leukemia","authors":"Jin Yang,&nbsp;Yan Zhang,&nbsp;Yue-Chu Li,&nbsp;Qing-Xin Wang,&nbsp;Meng-Yuan Zhang,&nbsp;Yu-Jing Xu,&nbsp;Jing-Jing Wang,&nbsp;Xiao-Ting Liang,&nbsp;Xiao-Long Jing,&nbsp;Shuang-Shuang Zhou,&nbsp;Qing-Qing Li,&nbsp;Zi-Xuan Wang,&nbsp;Yun Zhou,&nbsp;Nuo Qiao,&nbsp;Tian-Hua Wei,&nbsp;Ning Ding,&nbsp;Xin Xue,&nbsp;Yan-Cheng Yu,&nbsp;Xiao-Long Wang,&nbsp;Shan-Liang Sun,&nbsp;Wei-Chen Dai,&nbsp;Nian-Guang Li,&nbsp;Zhi-Hao Shi","doi":"10.1002/ddr.70022","DOIUrl":"https://doi.org/10.1002/ddr.70022","url":null,"abstract":"<div>\u0000 \u0000 <p>The abnormal overexpression of FLT3 kinase is intimately associated with pathogenesis of acute myeloid leukemia (AML), positioning FLT3 inhibitors as pivotal therapeutic agents. Despite the availability of three FDA-approved FLT3 inhibitors, their clinical utility is hampered by resistance stemming from tyrosine kinase domain (TKD) mutations. Through an integrative analysis of case studies, we identified a potential advantage of type I FLT3 inhibitors in overcoming TKD mutation-induced resistance. Structure–activity relationships (SAR) analysis indicated that <b>FW-1</b> exhibited over 50% inhibition against FLT3 at a concentration of 1 μM and demonstrated potent activity against AML cell lines MV4-11 (IC₅₀ = 2.68 μM) and MOLM-13 (IC₅₀ = 1.03 μM). In our cellular mechanistic studies, <b>FW-1</b> also effectively induced apoptosis by arresting cell cycle progression in the G0/G1 phase. This study introduces <b>FW-1</b> as a promising lead for type I FLT3 inhibitor, warranting further optimization.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 8","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling Immunotherapy Evasion in Lung Cancer: The Role of Fanconi Anemia and Stemness Genes in Shaping an Immunosuppressive Microenvironment","authors":"Haixia Wu,&nbsp;Yilin Yu,&nbsp;Hailun Huang,&nbsp;Gen Lin,&nbsp;Wei Wang,&nbsp;Jianyuan Huang,&nbsp;Zhaojun Yu,&nbsp;Deju Ye,&nbsp;Wu Chi,&nbsp;Xing Lin","doi":"10.1002/ddr.70020","DOIUrl":"https://doi.org/10.1002/ddr.70020","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 <p>The study aimed to investigate the fanconi anemia (FA)-related and stemness-related genes in lung cancer (LC) patients. Firstly, we identified stemness-related genes through weighted gene co-expression network analysis combined with TCGA database. Further combined stemness-related genes with FA-related genes to screen for prognostic-related genes. Risk score was constructed from the screened genes and comprehensive bioinformatics analyses were performed. Finally, single-cell data and in vitro experiment were used to validate our results. We screened a total of eight genes to construct a risk score. The risk score was an independent prognostic factor for LC. The validation results of multiple GEO databases were consistent with our results. Functional and pathway enrichment analysis showed that risk score was associated with cell cycle, DNA replication, DNA damage repair, and immune-related pathways. The results showed to be related to the stem cell self-renewal and proliferation. Besides, we also found that patients with higher risk scores had lower immune activity and function, and the effectiveness of immunotherapy might be poorer, with a higher rate of immune escape. Finally, our results revealed that SLC2A1 had the highest correlation with B cells in single-cell data analysis, and we validated its correlation with B cells and its expression with FA-related genes, tumor invasiveness, stemness, and drug sensitivity. Our research constructed a risk score based on FA-related and tumor stemness-related specific genes. In addition to accurately predicting the prognosis of patients with LC, the risk score may also serve as an innovative and viable predictor of immunotherapy response.</p>\u0000 </section>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 8","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Formulation and Characterization of RBCS Coated Carboplatin Loaded Nano-Liposomal Formulation for Managing Breast Cancer","authors":"Akhilesh Dubey,&nbsp;Faby Raju,&nbsp;Cynthia Lizzie Lobo,&nbsp;Ravi Gs,&nbsp;Srinivas Hebbar,&nbsp;Amitha Shetty,&nbsp;Pankaj Kumar,&nbsp;Sally A. El-Zahaby","doi":"10.1002/ddr.70019","DOIUrl":"10.1002/ddr.70019","url":null,"abstract":"<div>\u0000 \u0000 <p>Cell membrane-coated Nano-Liposomes (CM-NLPs) offer a promising approach that combines the advantages of both host cells and synthetic nano-liposomes (NLPs). This technique involves coating liposomes with red blood cell (RBC) membranes to enhance their functionality. In this study, novel carboplatin-loaded NLPs (CP-NLPs) were formulated using phospholipids (Soya Phosphatidyl Choline) and cholesterol through the thin-film hydration method, and optimized using a 3² full factorial design. The optimized CP-NLPs were coated with RBC membranes, resulting in the formulation “CP-RBCs-NLPs.” These were characterized for particle size, zeta potential, entrapment efficiency, transmission electron microscopy (TEM), differential scanning calorimetry (DSC), protein content, in vitro drug release, cell viability, and stability. The optimized CP-RBCs-NLPs exhibited a particle size of 103.6 nm, with zeta potential values of −27.3 mV indicating good stability. The entrapment efficiency was approximately 56%, and the drug release profile showed sustained release for up to 8 h. Cytotoxicity studies in human triple-negative breast cancer (MDA-MB468) cell lines demonstrated that CP-RBCs-NLPs effectively delivered the drug into target cells, facilitating cell death due to their bilayer structure similar to cell membranes. Overall, CP-RBCs-NLPs outperformed both carboplatin-loaded conventional NLPs (CP-CNLPs) and carboplatin-conventional solution (CP-CNS), making it a superior formulation for drug delivery.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 8","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New Ester-Containing Azole Derivatives With Potent Anti-Candida Effects: Synthesis, Antifungal Susceptibility, Cytotoxicity, and Molecular Modeling Studies","authors":"Yusuf Ataker,&nbsp;Özge Öncü,&nbsp;Dolunay Gülmez,&nbsp;Suna Sabuncuoğlu,&nbsp;Sevtap Arikan-Akdagli,&nbsp;Suat Sari","doi":"10.1002/ddr.70021","DOIUrl":"10.1002/ddr.70021","url":null,"abstract":"<div>\u0000 \u0000 <p>Mortalities due to mycoses have dramatically increased with the emergence of drug-resistant strains and growing immune-compromised populations globally. Azole antifungals have been the first choice against fungal infections of a wide spectrum and several azole derivatives with ester function were reported for their potentially promising and favorable activity against <i>Candida</i> spp. In this study, we designed and synthesized a series of 1-(aryl)−2-(1<i>H</i>-imidazol-1-yl/1<i>H</i>-1,2,4-triazol-1-yl)ethyl esters, and tested them against seven reference <i>Candida</i> strains using EUCAST reference microdilution method. Among the series, <b>6a</b>, <b>6d</b>, and <b>6g</b> proved highly potent in vitro compared to fluconazole; especially against <i>Candida albicans</i> and <i>Candida tropicalis</i> with minimum inhibitor concentration (MIC) values as low as 0.125 and 0.06 mg/L, respectively, although their activities against <i>Candida krusei</i> and <i>Candida glabrata</i> remained limited. The compounds also showed minimal toxicity to murine fibroblasts according to the in vitro cytotoxicity tests. Molecular modeling predicted <b>6g</b> as an orally available druglike compound according to all parameters and CYP51 inhibition as the likely mechanism for their antifungal effects. The study underpins the promise of azoles with ester functionality as a potential scaffold for small-molecule antifungal drug design.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ambroxol Improves Amyloidogenic, NF-κB, and Nrf2 Pathways in a Scopolamine-Induced Cognitive Impairment Rat Model of Alzheimer's Disease","authors":"Khushboo Govind Faldu,&nbsp;Jigna Samir Shah","doi":"10.1002/ddr.70017","DOIUrl":"10.1002/ddr.70017","url":null,"abstract":"<div>\u0000 \u0000 <p>Ambroxol (ABX) is used to manage excessive production of mucus in the respiratory system. The present study sought to assess the neuroprotective potential of ambroxol by influencing the amyloidogenic, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways in a rat model of Alzheimer's disease (AD) induced by scopolamine. The AD pathology was induced by chronic administration of scopolamine. The rats were given scopolamine at a dose of 2 mg/kg via intraperitoneal injection daily for 14 days, followed by treatment (ABX 121.5, 135, and 180 mg/kg orally and 5 mg/kg orally of donepezil) for the next 28 days while continuing to receive daily scopolamine injection. The behavior of the rats was evaluated using Modified Y-Maze and Novel object recognition tasks. Analyses were carried out on AD pathological markers [Amyloid beta peptide 1-40, Amyloid beta peptide 1-42, acetylcholinesterase, beta-secretase 1 (BACE1), total tau, and p-tau], inflammatory markers [NF-κB, tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interferon γ], antioxidant markers (Nrf2 and heme Oxygenase 1 (HO-1)], along with synaptophysin and glial fibrillary acidic protein (GFAP) immunohistochemistry and histopathological assessment of the hippocampus. Our findings indicated that ABX reduced impairment in behavior. Levels of Acetylcholinesterase, BACE1, amyloid beta 1-40, amyloid beta 1-42, total tau, p-tau, NF-κB, IFN-γ, IL-6, and TNF-α decreased significantly. There was a significant increase in the levels of HO-1 and Nrf2. It stopped the neuronal degeneration, raised synaptophysin immunoreactivity, and lowered GFAP immunoreactivity. The current research indicates that ambroxol may possess senomorphic properties by impacting the transcription factors NF-κB and senescence-associated secretory phenotype (SASP). Consequently, it could provide neuroprotection through alterations in the Nrf2 and NF-κB signaling pathways in AD.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of Novel SIRT3 Inhibitors for the Cancer Differentiation Therapy by Structural Modification","authors":"Honggang Li,&nbsp;Yanmei Du,&nbsp;Lihui Zhang,&nbsp;Guangzhao Xu,&nbsp;Fahui Li,&nbsp;Daopeng Zhang,&nbsp;Lei Zhang","doi":"10.1002/ddr.70016","DOIUrl":"10.1002/ddr.70016","url":null,"abstract":"<div>\u0000 \u0000 <p>Inhibition of SIRT3 triggered differentiation of multiple myeloma (MM) cells. In discovery of potent SIRT3 inhibitors for cancer differentiation therapy, structural modification was performed on the previously developed lead compound <b>S27</b>. A total of 49 compounds divided into two series were designed and synthesized. In the enzyme inhibitory assay, several molecules (<b>A7</b>, <b>A13</b>, <b>B15</b>, and <b>B26</b>) exhibited potent SIRT3 inhibitory activity and selectivity. Significantly, representative compounds, especially <b>A7</b>, promoted differentiation of MM cells from cancer phenotype to normal cells, accompanied by increased expression of antigen CD49e, human immunoglobulin light chain λ-IgLG and κ-IgLG. Additionally, molecule <b>A7</b> reversed growth factor IL-6 induced MM cell proliferation, improved the antiproliferative activity of Ixazomib and increased the apoptotic rate of MM cells treated with Ixazomib. Collectively, potent SIRT3 inhibitors with MM cell differentiation potency were developed for the cancer therapy used alone or in combination.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}