ChemMedChem最新文献_第4页

Small Molecule-Mediated Photothermal Therapy Induces Apoptosis in Cancer Cells. 小分子介导的光热疗法诱导癌细胞凋亡。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-05-09 DOI: 10.1002/cmdc.202500151

Asima Sahu, Jaypalsing Ingle, Reha Panigrahi, Sudipta Basu

{"title":"Small Molecule-Mediated Photothermal Therapy Induces Apoptosis in Cancer Cells.","authors":"Asima Sahu, Jaypalsing Ingle, Reha Panigrahi, Sudipta Basu","doi":"10.1002/cmdc.202500151","DOIUrl":"10.1002/cmdc.202500151","url":null,"abstract":"Cancer remains as one of the most life-threatening diseases in the whole world. Most of the therapeutic strategies to eradicate cancer are highly invasive, leading to severe injury and trauma to the patients. In recent times, phototherapy has emerged as one of the noninvasive therapeutic strategies for cancer treatment. However, development of novel small-molecule photothermal agents remains a major challenge. To address this, herein, a small molecule library having aromatic substituted-3-methoxy-pyrrole and 2-(3-cyano-4,5,5-trimethylfuran-2(5 H)-ylidene) malononitrile in a concise synthetic strategy is designed and synthesized. One of the library members (7H) self-assembles into spherical-like nanoparticles having <100 nm size in water and is found to exhibit remarkable increase in temperature under 740 nm near-infrared (NIR) light. Interestingly, compound 7H homes into the lysosomal compartments and the lipid droplets in the HCT-116 colon cancer cells within 3 h and induces photothermal effect followed by generation of reactive oxygen species while irradiating under 740 nm NIR light for 10 min. Moreover, 7H triggers programmed cell death (apoptosis) to induce remarkable HCT-116 cell killing. This small molecule-mediated photothermal effect shows potential to be an interesting tool for the next-generation noninvasive cancer phototherapy.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e2500151"},"PeriodicalIF":3.6,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957352","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}

引用次数: 0

Evaluating Bis-Phenacyl Bromide-Based Bis-Heterocyclic Templates as Anticancer Prototypes and Potential PARP1 Inhibitors. 评估基于双苯基溴的双杂环模板作为抗癌原型和潜在的PARP1抑制剂。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-05-09 DOI: 10.1002/cmdc.202500045

Refaie M Kassab, Mohamed A M Ali, Sami A Al-Hussain, Magdi E A Zaki, Zeinab A Muhammad, Alyaa S Abdel Halim

{"title":"Evaluating Bis-Phenacyl Bromide-Based Bis-Heterocyclic Templates as Anticancer Prototypes and Potential PARP1 Inhibitors.","authors":"Refaie M Kassab, Mohamed A M Ali, Sami A Al-Hussain, Magdi E A Zaki, Zeinab A Muhammad, Alyaa S Abdel Halim","doi":"10.1002/cmdc.202500045","DOIUrl":"10.1002/cmdc.202500045","url":null,"abstract":"Poly(ADP-ribose) polymerase 1 (PARP1) plays a pivotal role in DNA damage repair and represents a promising antineoplastic target. Novel bis-heterocyclic derivatives based on a bis-phenacyl bromide scaffold were synthesized and assessed for their antineoplastic potential against eight malignant cell lines, and PARP1 inhibitory activity. These derivatives exhibited selective cytotoxicity toward MCF7 and PC-3 cancer cell lines, while showing limited or no toxicity to other malignant cell lines. Derivatives 5a-e, 13, 18, 34, 35, and 36 (IC50 < 10 μM) were most effective against PC-3 cells. Derivatives 5a, 5d, 5e, 12, 25, 28a and 34 demonstrated remarkable potency against MCF7 cells (IC50 = 0.006-0.417 μM), surpassing the efficacy of doxorubicin. Mechanistic investigations indicated that their cytotoxicity involved programmed cell death induction, as evidenced by increased protein expression of caspase-7, cytochrome C, BAX, and p53, as well as reduced BCL-2 protein levels, along with sub-G1 cell cycle cessation via cyclin-dependent kinase genes expression downregulation. All derivatives showed PARP1 inhibitory activity, with 5a-e, 8a, 13, 34, and 36, outperforming olaparib with sub-nanomolar IC50 values. Molecular docking revealed that the derivatives docked well with PARP1, consistent with enzymatic inhibition data. Our findings support further optimization of these bis-heterocyclic scaffolds as next-generation anticancer agents and potent PARP1 inhibitors.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e2500045"},"PeriodicalIF":3.6,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953944","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}

引用次数: 0

Front Cover: Novel Sulfonamide-Sydnone Hybrids: Complementary Insight into Anti-Inflammatory Action, Anti-SARS-CoV-2 Activity, Human Serum Albumin Interaction, and in silico Analysis (ChemMedChem 9/2025) 封面：新型磺胺- sydnone复合物：抗炎作用、抗sars - cov -2活性、人血清白蛋白相互作用和硅分析的互补洞察（ChemMedChem 9/2025）

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-05-07 DOI: 10.1002/cmdc.202580901

Igor Resendes Barbosa, Mayara Alves Amorim, Vitor Hélio de Souza Oliveira, Eunice André, Guilherme Pereira Guedes, Otávio Augusto Chaves, Carlos Serpa, Natalia Fintelman-Rodrigues, Carolina Q. Sacramento, Thiago Moreno L. Souza, Carlos Mauricio R. Sant'Anna, Aurea Echevarria

{"title":"Front Cover: Novel Sulfonamide-Sydnone Hybrids: Complementary Insight into Anti-Inflammatory Action, Anti-SARS-CoV-2 Activity, Human Serum Albumin Interaction, and in silico Analysis (ChemMedChem 9/2025)","authors":"Igor Resendes Barbosa, Mayara Alves Amorim, Vitor Hélio de Souza Oliveira, Eunice André, Guilherme Pereira Guedes, Otávio Augusto Chaves, Carlos Serpa, Natalia Fintelman-Rodrigues, Carolina Q. Sacramento, Thiago Moreno L. Souza, Carlos Mauricio R. Sant'Anna, Aurea Echevarria","doi":"10.1002/cmdc.202580901","DOIUrl":"https://doi.org/10.1002/cmdc.202580901","url":null,"abstract":"Novel sulfonamide-sydnone hybrids are designed and synthesized as potential anti-SARS-CoV-2 and anti-inflammatory. Cell-based assays indicate that the sulfonamide moiety in para-position related to the phenyl ring attached to the sydnone heterocycle core have better antiviral potency than the meta-position substitution, targeting the main protease (Mpro) of SARS-CoV-2 via a non-competitive way. More details can be found in article 10.1002/cmdc.202400697 by Aurea Echevarria and co-workers.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture>\u0000 </div>\u0000 </figure>\u0000 ","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.202580901","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synthesis and Biological Evaluation of Bicyclic Pyrazolines with Promising Antimicrobial Activities. 具有抗菌活性的双环吡唑啉类化合物的合成及生物学评价。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-05-07 DOI: 10.1002/cmdc.202500144

Debora Caviglia, Anna Maria Schito, Susanna Penco, Chiara Brullo, Marcus Baumann

引用次数: 0

Novel Para-Phenylenediamine-Based Derivatives as Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1) Inhibitors: An In Vitro Preliminary Characterization. 新型对苯二胺衍生物作为受体酪氨酸激酶样孤儿受体1 （ROR1）抑制剂：体外初步表征。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-05-06 DOI: 10.1002/cmdc.202500247

Gerardina Smaldone, Maria Rosaria Miranda, Francesca Di Matteo, Valeria Napolitano, Michela Aliberti, Simona Musella, Veronica Di Sarno, Gianluigi Lauro, Giuseppe Bifulco, Giacomo Pepe, Giovanna Aquino, Mario Felice Tecce, Isabel Maria Gomez-Monterrey, Pietro Campiglia, Carmine Ostacolo, Alessia Bertamino, Vincenzo Vestuto, Tania Ciaglia

{"title":"Novel Para-Phenylenediamine-Based Derivatives as Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1) Inhibitors: An In Vitro Preliminary Characterization.","authors":"Gerardina Smaldone, Maria Rosaria Miranda, Francesca Di Matteo, Valeria Napolitano, Michela Aliberti, Simona Musella, Veronica Di Sarno, Gianluigi Lauro, Giuseppe Bifulco, Giacomo Pepe, Giovanna Aquino, Mario Felice Tecce, Isabel Maria Gomez-Monterrey, Pietro Campiglia, Carmine Ostacolo, Alessia Bertamino, Vincenzo Vestuto, Tania Ciaglia","doi":"10.1002/cmdc.202500247","DOIUrl":"10.1002/cmdc.202500247","url":null,"abstract":"ROR1 kinase is an underexplored promising target for the development of novel anticancer drugs, being strongly expressed in several cancer cell lines, but poorly in non-tumor cells. This property, together with the scarce number of molecules effective against ROR1, leads to the design and development of a research program aimed at the discovery of new chemical entities able to inhibit ROR1 thus interfering with its protumoral activity. Step-by-step in silico studies guide the design and synthesis of para-phenylenediamine-based compounds. Surface plasmon resonance and Cellular Thermal Shift Assay analyses, coordinated with cytotoxicity assays carried out on JeKo-1 (mantle cell lymphoma) and SH-SY5Y (neuroblastoma cell) cell lines, demonstrate the strong affinity and the anticancer potential of the derivative 17, respectively, further confirming its mechanism of action. Moreover, pharmacokinetic assessment reveals a good stability profile for derivative 17, paving the way for additional SAR studies on the para-phenylenediamine as a scaffold for developing new ROR1 inhibitors.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e2500247"},"PeriodicalIF":3.6,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959213","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}

引用次数: 0

Structure-Activity Relationships of New 1-Aryl-1H-Indole Derivatives as SARS-CoV-2 Nsp13 Inhibitors. 新型1-芳基- 1h -吲哚衍生物作为SARS-CoV-2 Nsp13抑制剂的构效关系

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-05-05 DOI: 10.1002/cmdc.202500205

Valentina Noemi Madia, Roberta Emmolo, Elisa Patacchini, Donatella Amatore, Stefania Maloccu, Davide Ialongo, Aurora Albano, Giuseppe Ruggieri, Emanuele Cara, Laura Zarbo, Antonella Messore, Riccardo De Santis, Alessandra Amoroso, Florigio Lista, Francesca Esposito, Enzo Tramontano, Angela Corona, Roberto Di Santo, Roberta Costi

{"title":"Structure-Activity Relationships of New 1-Aryl-1H-Indole Derivatives as SARS-CoV-2 Nsp13 Inhibitors.","authors":"Valentina Noemi Madia, Roberta Emmolo, Elisa Patacchini, Donatella Amatore, Stefania Maloccu, Davide Ialongo, Aurora Albano, Giuseppe Ruggieri, Emanuele Cara, Laura Zarbo, Antonella Messore, Riccardo De Santis, Alessandra Amoroso, Florigio Lista, Francesca Esposito, Enzo Tramontano, Angela Corona, Roberto Di Santo, Roberta Costi","doi":"10.1002/cmdc.202500205","DOIUrl":"10.1002/cmdc.202500205","url":null,"abstract":"It has been more than four years since the first report of SARS-CoV-2, the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic, the scientific community is focused on vaccine development in an exceptionally rapid time frame, as well as the evaluation of a wide range of potential treatments in clinical trials, a few of which have also reached the market. However, these drugs are characterized by several limits (including low response to treatment in some patients, low effectiveness against the new variants, severe side effects, etc.), thus underscoring the need to speed up the research. Among potential antiviral targets, the SARS-CoV-2 nonstructural protein 13 (nsp13) is highly promising thanks to its pivotal role in viral replication. Pursuing the studies on the development of nsp13 inhibitors, herein, the design, synthesis, and biological evaluation of new SARS-CoV-2 nsp13 inhibitors are reported. In general, the newly designed dikehexenoic derivatives are proven active against both the enzymatic activities showing measurable IC50 under 30 μM concentration, while the diketobutanoic series shows less promising results. Moreover, the tested compounds are capable of blocking viral replication without exerting cytotoxicity. Docking studies predict their binding into an allosteric pocket within the RecA2 domain.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e2500205"},"PeriodicalIF":3.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953793","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}

引用次数: 0

Marine-Inspired Spirooxindole PIM-1 Kinase Inhibitors Endowed with Concomitant TRKA/CDK2 Inhibition for Multifaceted Non-Small Cell Lung Cancer Apoptotic Induction. 海洋激发的螺霉哚PIM-1激酶抑制剂具有伴随TRKA/CDK2抑制作用，可诱导多方面的NSCLC凋亡。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-05-04 DOI: 10.1002/cmdc.202500028

Refaah M Al-Jassas, Mohammad Shahidul Islam, Abdullah Mohammed Al-Majid, Matti Haukka, Mohamed S Nafie, Marwa M Abu-Serie, Mohamed Teleb, Marwa M Shaaban, Abdul Majeed Abdullah Alayyaf, Luis R Domingo, Sajda Ashraf, Zaheer Ul-Haq, Yasmine M Abdel Aziz, Assem Barakat

{"title":"Marine-Inspired Spirooxindole PIM-1 Kinase Inhibitors Endowed with Concomitant TRKA/CDK2 Inhibition for Multifaceted Non-Small Cell Lung Cancer Apoptotic Induction.","authors":"Refaah M Al-Jassas, Mohammad Shahidul Islam, Abdullah Mohammed Al-Majid, Matti Haukka, Mohamed S Nafie, Marwa M Abu-Serie, Mohamed Teleb, Marwa M Shaaban, Abdul Majeed Abdullah Alayyaf, Luis R Domingo, Sajda Ashraf, Zaheer Ul-Haq, Yasmine M Abdel Aziz, Assem Barakat","doi":"10.1002/cmdc.202500028","DOIUrl":"10.1002/cmdc.202500028","url":null,"abstract":"Several aspects of apoptosis signaling have been explored for managing non-small cell lung cancer (NSCLC). While inhibiting oncogenic kinases like PIM-1 and CDK2 has shown promise, clinical success remains limited. Recently, targeting TrkA gains attention following FDA approval of Entrectinib and Larotrectinib for NSCLC. In this study, a multitarget strategy is designed to simultaneously inhibit PIM-1, CDK2, and TrkA using hybrid ligands inspired by Saccharomonosporine A, a marine-derived oxindole-based metabolite. The hybrid scaffold incorporates spirooxindole derivatives with structural elements of CDK2 and TrkA inhibitors. A one-pot [3 + 2] cycloaddition reaction produces a series of pyrazole-clubbed spirooxindoles. Single-crystal X-ray diffraction and molecular electron density studies confirm product structures and propose reaction mechanisms. MTT assay against A549 NSCLC cells identifies compounds 6e, 6h, 7b, 7e, and 7f as potent and selective inhibitors, with IC50 values ranging from 0.022 to 0.098 μm and selectivity indices of 3.99-29.36. Compounds 6e and 7f emerge as the most balanced inhibitors of PIM-1 (IC50 = 3.9, 4.6 nm), CDK2, and TrkA. Molecular docking and dynamics simulations highlight key interactions stabilizing these compounds. 7f, the most potent cytotoxic spirooxindole derivative, disrupted the A549 cell cycle and induced apoptosis by 53-fold%. Accordingly, compound 7f can be further developed as anti-lung cancer chemotherapeutic with Trka/PIM-1/CDK2 inhibition pathway.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e2500028"},"PeriodicalIF":3.6,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951534","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}

引用次数: 0

Development of Cyclic Peptide-Based Radiotracers for uPAR 环肽基uPAR放射性示踪剂的研制。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-05-01 DOI: 10.1002/cmdc.202500061

Xingkai Wang, Xu Zhang, Siqi Zhang, Lulu Zhang, Jieting Shen, Yingzi Zhang, Hailong Zhang, Ming-Rong Zhang, Rui Wang, Kuan Hu

{"title":"Development of Cyclic Peptide-Based Radiotracers for uPAR","authors":"Xingkai Wang, Xu Zhang, Siqi Zhang, Lulu Zhang, Jieting Shen, Yingzi Zhang, Hailong Zhang, Ming-Rong Zhang, Rui Wang, Kuan Hu","doi":"10.1002/cmdc.202500061","DOIUrl":"10.1002/cmdc.202500061","url":null,"abstract":"The urokinase plasminogen activator (uPA) system has garnered attention as a promising biomarker, with the uPA receptor (uPAR) playing a central role in system regulation and demonstrating strong associations with tumorigenicity, invasion, and metastasis. Radioligands targeting uPAR have emerged as powerful tools for the early diagnosis and treatment of malignant tumors. In this study, we developed and evaluated three novel cyclic peptide-based positron emission tomography (PET) radioligands, denoted as [⁶⁴Cu]CARP-1, [⁶⁴Cu]CARP-2, and [⁶⁴Cu]CARP-3, for uPAR imaging. These radioligands differ in the chiral configuration of their disulfide bond crosslinkers, which influences their binding ability and pharmacokinetic profiles. Among the three, [⁶⁴Cu]CARP-2 demonstrated optimal tumor radioactivity accumulation, specificity, and favorable pharmacokinetics in an MC38 tumor-bearing mouse model. Compared to [⁶⁴Cu]DOTA-AE105, a well-characterized radiotracer currently under clinical investigation, [⁶⁴Cu]CARP-2 exhibited reduced non-specific uptake and rapid clearance from normal tissues. These attributes highlight its potential as a diagnostic tool with improved imaging accuracy. The promising preclinical performance of [⁶⁴Cu]CARP-2 underscores its potential for further clinical investigation as a uPAR-targeting radiotracer.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 10","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954125","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}

引用次数: 0

Inhibition of Adenosine Triphosphate Production in Pancreatic Cancer Cells by a Library of N-(1H-Indol-4-ylmethyl)benzenesulfonamide and N-(1H-Indol-5-ylmethyl)benzenesulfonamide Analogs. N-（1h -吲哚-4-甲基）苯磺酰胺和N-（1h -吲哚-5-甲基）苯磺酰胺类似物库对胰腺癌细胞ATP生成的抑制作用

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-04-28 DOI: 10.1002/cmdc.202500136

Ryan C Witt, Caroline E Dunn, Levi A Zanders, Adeleye A Edema, Sakariyau A Waheed, Carina A Derewonko, Lauren C Franzen, Presley L Osborn, Jenna D Caudle, Robert J Sheaff, Angus A Lamar

{"title":"Inhibition of Adenosine Triphosphate Production in Pancreatic Cancer Cells by a Library of N-(1H-Indol-4-ylmethyl)benzenesulfonamide and N-(1H-Indol-5-ylmethyl)benzenesulfonamide Analogs.","authors":"Ryan C Witt, Caroline E Dunn, Levi A Zanders, Adeleye A Edema, Sakariyau A Waheed, Carina A Derewonko, Lauren C Franzen, Presley L Osborn, Jenna D Caudle, Robert J Sheaff, Angus A Lamar","doi":"10.1002/cmdc.202500136","DOIUrl":"10.1002/cmdc.202500136","url":null,"abstract":"A library of 50 indolyl sulfonamides and 9 amide analogs based upon the 4-indolyl and 5-indolyl frameworks has been synthesized to target the metabolic processes of pancreatic cancer. Thirteen of the 50 compounds are identified as cytotoxic at 50 μM using a traditional (48-h compound exposure) assay against 7 pancreatic cancer cell lines and 1 noncancerous cell line. The potential role of the compounds as metabolic inhibitors of adenosine triphosphate (ATP) production is then evaluated using a rapid screening (1-2 h compound exposure) assay developed within our laboratories. The rapid assay identifies ten compounds as strong or moderate hits at 3 μM against the panel of pancreatic and noncancerous cell lines. The IC50 values of the active compounds are determined using the rapid assay in the absence of glucose and four of the compounds display an IC50 value <1 μM against one or more pancreatic cancer cell lines. A comparison of IC50 values of the active compounds in the presence of glucose implicates the potential role of the compounds as oxidative phosphorylation inhibitors of ATP production. Finally, a series of amide analogs are synthesized and screened for activity to determine the structural importance of the sulfonamide functionality.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e2500136"},"PeriodicalIF":3.6,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957783","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}

引用次数: 0

Beyond Docking: A Multi-Tier Computational Pipeline for USP7 Inhibitor Optimization. 超越对接：USP7抑制剂优化的多层计算管道。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-04-27 DOI: 10.1002/cmdc.202500210

Serdar Durdagi, Ehsan Sayyah, Muhammet Eren Ulug, Serdar Durdağı

{"title":"Beyond Docking: A Multi-Tier Computational Pipeline for USP7 Inhibitor Optimization.","authors":"Serdar Durdagi, Ehsan Sayyah, Muhammet Eren Ulug, Serdar Durdağı","doi":"10.1002/cmdc.202500210","DOIUrl":"https://doi.org/10.1002/cmdc.202500210","url":null,"abstract":"Ubiquitin-specific protease 7 (USP7) is a key deubiquitinating enzyme involved in tumor suppression, DNA repair, and epigenetic regulation. Given its critical role in cancer progression, USP7 has emerged as an attractive therapeutic target. In this study, we employed a multi-tier computational approach, integrating ligand-based virtual screening, molecular docking, MD simulations, MM/GBSA binding free energy calculations, binary QSAR modeling, and steered MD simulations to identify and optimize novel USP7 inhibitors. Using SwissSimilarity-based ligand screening, we selected structurally related analogs of previously identified and validated hit compounds by our research group and performed grid-based docking simulations, prioritizing molecules with high binding affinity (docking scores < -8.0 kcal/mol). The top-ranked candidates were refined through long-term MD simulations and MM/GBSA free energy calculations to assess their structural stability and interaction patterns with key USP7 residues. Binary QSAR analysis further evaluated the anticancer potential of these compounds, filtering those with high predicted therapeutic activity (normalized therapeutic activity value > 0.5). Furthermore, to investigate selectivity of the potent compounds, we performed cross-docking against multiple USP family members. Finally, sMD simulations provided insights into the mechanical stability of ligand-protein interactions. The identified candidates hold promise for further in vitro studies, advancing USP7-targeted therapies for cancer treatment.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500210"},"PeriodicalIF":3.6,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143960606","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}

引用次数: 0