Journal of Medicinal Chemistry最新文献

{"title":"Evaluation of Dynamic Light Scattering as an Effective Quality Control Method for Aggregates in Radiolabeled Antibodies","authors":"Huu Bao Nguyen, Hyun Park, Jeong Eun Lim, Thuy Tien Nguyen, Hwan Hui Kim, Kyeongwon Kim, Jung Young Kim, Kyo Chul Lee, Jeongsoo Yoo","doi":"10.1021/acs.jmedchem.4c02344","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02344","url":null,"abstract":"Radiolabeled antibodies are promising for targeted cancer imaging, but their structural integrity may suffer during bioconjugation and radiolabeling, leading to undetected aggregation. This study evaluates dynamic light scattering (DLS) as a complementary method to size-exclusion high-performance liquid chromatography (SEC-HPLC) for detecting aggregation in radiolabeled antibodies. Trastuzumab was conjugated with a NOTA bifunctional chelator at various ratios, radiolabeled with [⁶⁴Cu]CuCl₂, and analyzed by using DLS and SEC-HPLC before and after purification. DLS revealed significant aggregation during preparation, undetected by SEC-HPLC, and showed reduced aggregates following purification. Tumor-targeting efficacy correlated with intact antibody content, with Pearson’s correlations of 0.71 (PET imaging) and 0.75 (biodistribution) in NIH3T6.7 tumor-bearing mice. The findings suggest DLS as a vital quality control tool, offering enhanced detection of antibody aggregation. By adopting DLS, the bioactivity of radiolabeled antibodies can be better predicted, potentially improving the reliability and effectiveness of these radiopharmaceuticals in clinical settings.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"122 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Guardians at the Gate: Optimization of Small Molecule Entry Inhibitors of Ebola and Marburg Viruses","authors":"Malaika D. Argade, Jazmin Galván Achi, Ryan Bott, Kimberly M. Morsheimer, Callum D. Owen, Christian A. Zielinski, Arsen M. Gaisin, Mario Alvarez, Terry W. Moore, Fan Bu, Fang Li, Michael Cameron, Manu Anantpadma, Robert A. Davey, Norton P. Peet, Lijun Rong, Irina N. Gaisina","doi":"10.1021/acs.jmedchem.4c01646","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01646","url":null,"abstract":"Ebola and Marburg (EBOV and MARV) filoviral infections lead to fatal hemorrhagic fevers and have caused over 30 outbreaks in the last 50 years. Currently, there are no FDA-approved small molecule therapeutics for effectively treating filoviral diseases. To address this unmet medical need, we have conducted a systematic structural optimization of an early lead compound, <i>N</i>-(4-(4-methylpiperidin-1-yl)-3-(trifluoromethyl)phenyl)-4-(morpholinomethyl)benzamide (<b>1</b>), borne from our previously reported hit-to-lead effort. This secondary round of structure–activity relationship (SAR) involved the design and synthesis of several deconstructed and reconstructed analogs of compound <b>1</b>, which were then tested against pseudotyped EBOV and MARV. The antiviral activities of the most promising leads were further validated in infectious assays. The optimized analogs exhibited desirable antiviral activity against different ebolaviruses and reduced off-target activity. Additionally, they also possessed druglike properties, that make them ideal candidates for <i>in vivo</i> efficacy studies as part of our ongoing drug discovery campaign against EBOV and MARV.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"251 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Precise Carrier-Free Pt(IV)-Nanobombs for Apoptosis/Ferroptosis Synergistic Tumor Therapy: A New Effective Method to Obtain Good Chemotherapy and Low Toxicity","authors":"Xu Guo, Xue-Jiao Liang, Jia-Le Liu, Zhi-Hui Li, Zhihao You, Dandan Zhao, Yali Song, Longfei Li, Xue-Qing Song","doi":"10.1021/acs.jmedchem.4c02034","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02034","url":null,"abstract":"The emerged apoptosis/ferroptosis synergistic platinum-based therapy has attracted a lot of attention but is far from clinic use due to high systemic toxicity. Herein, a series of novel precise carrier-free self-assembled platinum(IV) nanoparticles with lipid regulation effect named FSPNPs (<b>5</b>NPs–<b>8</b>NPs) were constructed via connecting fenofibrate acid (FA) to cisplatin or oxaliplatin-derived platinum(IV)-intermediates with disulfide bonds. FSPNPs can be stimulated by high-glutathione/ascorbic acid and acidity environment to produce an “explosion-like” cascade release process. Cell-activity showed precision of FSPNPs, which accumulated more in tumor cells and inhibited cell proliferation. Especially, <b>5</b>NPs have higher cell selectivity than cisplatin. FSPNPs downregulated glutathione/glutathione peroxidase 4, increased reactive oxygen species/lipid peroxidation/malondialdehyde, induced DNA damage/S-phase arrest, and regulated p53/Bcl-2/Bax to trigger the apoptosis/ferroptosis hybrid pathway. The released FA and derivates were docked into the peroxisome proliferator-activated receptor α with activating cholesterol metabolism to destroy membrane integrity. FSPNPs also showed good biocompatibility and superior antitumor activity with no observable tissue damage.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"2 3 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antibody-Vincristine Conjugates as Potent Anticancer Therapeutic Agents","authors":"Agathe Boos, Julien Most, Héloïse Cahuzac, Louis Moreira da Silva, François Daubeuf, Stéphane Erb, Sarah Cianférani, Oscar Hernandez-Alba, Constantin Semenchenko, Igor Dovgan, Sergii Kolodych, Alexandre Detappe, Françoise Dantzer, Alain Wagner, Maria Zeniou, Guilhem Chaubet","doi":"10.1021/acs.jmedchem.4c02425","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02425","url":null,"abstract":"Antibody-drug conjugates (ADCs) are a well-established class of therapeutics primarily used in oncology to selectively deliver highly cytotoxic agents into cancer cells. While ADCs should theoretically spare healthy tissues and diminish side effects in patients, off-target toxicity is still observed, all the more serious, as the drugs are extremely potent. In the quest toward safer payloads, we used the conventional chemotherapeutic drug vincristine to develop antibody-vincristine conjugates. Vincristine was <i>N</i>-alkylated with a cleavable linker and the resulting linker-payload conjugated to free cysteines of antibodies. We show that trastuzumab-vincristine conjugates display subnanomolar potency in vitro on HER2-positive cells, 2 orders of magnitude lower than free vincristine and comparable with marketed ADC. In vivo, trastuzumab-vincristine conjugates led to remarkable efficacy when compared to two standards of care, with complete tumor regression just 9 days after single administration. This highlights the untapped potential of the chemotherapeutic arsenal toward the development of novel ADC.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"47 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of N-Phenyl-5-propyl-1H-pyrazole-3-carboxamide, with Selective Inhibition and Degradation of HDAC6 for the Treatment of Acute Liver Injury","authors":"Hao Cui, Guodong Zhang, Liyuan Zhang, Shilong Sun, Kang Yang, Aixin Gen, Penfeng Wang, Hui Wang, Qing-Qing Zhou, Hongmei Li, Yadong Chen, Yuqin Yao, Tao Lu, Lei Zhang, Yong Zhu","doi":"10.1021/acs.jmedchem.4c02341","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02341","url":null,"abstract":"Acute liver injury is a severe and potentially life-threatening condition. Currently, there are no specific effective treatments available. HDAC6 has been identified as a promising strategy for treating ALI by inhibiting necrosis and inflammation. In this study, a series of pyrazole derivatives were designed to specifically target HDAC6, among which compound <b>6</b> demonstrated high antinecroptotic activity (IC₅₀ = 0.5 nM) and excellent selective HDAC6 inhibition (IC₅₀ = 4.95 nM, HDAC1/HDAC6 = 251). Surprisingly, compound <b>6</b> also exhibited excellent HDAC6 degradation activity (DC₅₀ = 0.96 nM) through mechanistic studies. Additionally, it demonstrated strong inhibitory effects on inflammatory proteins TNF-α, IL-1β, and IL-6, indicating significant anti-inflammatory activity. Moreover, in a mouse model of acetaminophen (APAP)-induced acute liver injury, compound <b>6</b> exhibited significant therapeutic and protective efficacy at a dose of 40 mg/kg. These findings confirm that compound <b>6</b> is a promising lead structure for combating ALI-related diseases and warrants further investigation.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"57 1 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combinatorial Synthesis toward the Discovery of Highly Cytotoxic Fe(III) Complexes","authors":"Felix Niemeier, Lisa-Marie Servos, Zisis Papadopoulos, Nicolás Montesdeoca, Kaixin Ni, Sascha Heinrich, Johannes Karges","doi":"10.1021/acs.jmedchem.4c01875","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01875","url":null,"abstract":"Cancer remains one of the deadliest diseases worldwide, with some tumors proving difficult to treat and increasingly resistant to current therapies. Capitalizing on this, there is a need for new therapeutic agents with novel mechanisms of action. Among promising candidates, Fe(III) complexes have gained significant attention as potential chemotherapeutic agents. However, research on these compounds has been limited to a small number, leading to inefficiencies in drug discovery. This study addresses these limitations by developing a combinatorial library of 495 new Fe(III) complexes synthesized from aminophenol, hydroxybenzaldehyde, and pyridine derivatives. The compounds were screened for cytotoxicity against human breast adenocarcinoma and noncancerous fibroblasts, identifying a novel class of Fe(III) complexes with modest cancer cell selectivity. The lead compound effectively eradicated breast cancer tumor spheroids at low micromolar concentrations, highlighting the potential of this approach for rapid drug discovery.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"36 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-Based Development of Novel Spiro-Piperidine ASH1L Inhibitors","authors":"Guang Huang, Rhiannon Stevens, Devon G. Hucek, Trupta Purohit, Shuangjiang Li, Hongzhi Miao, Elise Trost, Geoff Hewett, Bradley Clegg, Se Ra Park, Krishani Rajanayake, Bo Wen, Duxin Sun, Tomasz Cierpicki, Jolanta Grembecka","doi":"10.1021/acs.jmedchem.4c01673","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01673","url":null,"abstract":"The absent, small, or homeotic-like 1 (ASH1L) protein is a histone lysine methyltransferase that plays a crucial role in various cancers, including leukemia. Despite representing an attractive therapeutic target, only one class of ASH1L inhibitors was identified to date. Herein, we report development of advanced ASH1L inhibitors targeting the catalytic SET domain, which were designed to access previously unexplored binding pocket on ASH1L. Extensive medicinal chemistry combined with structure-based design led to identification of <b>66s</b> (<b>AS-254s</b>), a highly potent and selective ASH1L inhibitor (IC₅₀ = 94 nM), representing substantially improved inhibitory activity over previously reported compounds targeting ASH1L. Furthermore, <b>66s</b> effectively blocked cell proliferation and induced apoptosis and differentiation in leukemia cells harboring <i>MLL1</i> translocations. Overall, this work provides a high-quality chemical probe targeting the catalytic SET domain of ASH1L with increased inhibitory activity and cellular efficacy to study biological functions of ASH1L and potentially to develop novel anticancer therapeutics.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"92 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent Advances of Metal Complexes in the Treatment of Hepatocellular Carcinoma","authors":"Zhongren Xu, Yu Liu, Jiaqi Yang, Fuwei Li, Wukun Liu","doi":"10.1021/acs.jmedchem.4c01850","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01850","url":null,"abstract":"Chemotherapy has long been used in the clinical management of hepatocellular carcinoma (HCC), driving the development of anticancer chemotherapy drugs. Platinum complexes have attracted significant attention and have led to the creation of a series of platinum-based drugs used in diverse cancer treatments, including HCC. However, the clinical use of platinum drugs faces critical challenges due to drug resistance and side effects. Consequently, ongoing efforts have been devoted to the continuous development of new metal complexes with antitumor properties, aiming to serve as effective alternatives for HCC treatment. In this Perspective, we summarize and highlight the progress and relevant mechanisms related to new metal complexes in the treatment of HCC over the past decade. The development of metal complexes has the potential to further expand the scope of chemotherapy applications for HCC.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"30 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 Biochemical Evaluation of Novel MLK3 Inhibitors: A Target Hopping Example","authors":"Pascal Sander, Martin P. Schwalm, Andreas Krämer, Lewis Elson, Alexander Rasch, Benedikt Masberg, Roland Selig, Adrian Sievers-Engler, Michael Lämmerhofer, Susanne Müller, Stefan Knapp, Wolfgang Albrecht, Stefan A. Laufer","doi":"10.1021/acs.jmedchem.4c02552","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02552","url":null,"abstract":"The human kinome has tremendous medical potential. In the past decade, mixed-lineage protein kinase 3 (MLK3) has emerged as an interesting and druggable target in oncogenic signaling. The important role of MLK3 has been demonstrated in several types of cancer. In a target hopping example we started with the focal adhesion kinase (FAK) inhibitor PF-431396 (<b>10</b>), which shows off-target activity toward MLK3. We were able to develop highly active compounds in the single digit nanomolar range for MLK3. Furthermore, we achieved a dramatic shift in selectivity from FAK to MLK3. Here we present a new chemical class of MLK3 inhibitors, including our lead compound <b>37</b> with an outstanding IC₅₀ value of &lt;1 nM in a biochemical MLK3 assay while simultaneously exhibiting kinome-wide selectivity.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"141 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Journal of Medicinal Chemistry Collection: Drug Discovery in Italy","authors":"Antonella Ciancetta, Maria Laura Bolognesi","doi":"10.1021/acs.jmedchem.4c02959","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02959","url":null,"abstract":"We are pleased to introduce a Collection on “Drug Discovery in Italy” on behalf of the &lt;i&gt;Journal of Medicinal Chemistry&lt;/i&gt;. Italy has a long tradition of excellence in drug discovery, with several drugs brought to the market. (1) Today, this tradition continues and the pharmaceutical sector is still one of the main drivers of the country’s economy. However, the sector is predominantly active in the production of active pharmaceutical ingredients (APIs), with only a few companies and highly specialized Contract Research Organizations (CROs) engaged in R&amp;D. The main dissemination efforts are therefore made by academic medicinal chemists, who try their best, despite a wavering support from the Italian Ministry of Universities and Research (MUR). The Medicinal Chemistry Division of the Italian Chemical Society (781 members in 2024) plays an active role in promoting collaboration between all the drug discovery stakeholders in Italy, and established a permanent roundtable in September 2023. (2) The current situation is mirrored in the 208 manuscripts with corresponding authors affiliated with an Italian institution that were accepted for publication between January 2020 and August 2024 in the &lt;i&gt;Journal of Medicinal Chemistry&lt;/i&gt;. An analysis based on institution type revealed that the majority (85%) of the publications feature corresponding authors working in academia, followed by contributions (9%) submitted by researchers working in national research centers or public research institutes managed by private foundations (e.g., the Italian Institute of Technology), and a minority (6%) of scientists working in industry. Interestingly, the majority (60%) of the publications from industry were contributed by researchers from Chiesi Farmaceutici S.p.A., whereas the other contributions were authored by researchers at Dompé Farmaceutici S.p.A. and Molecular Horizon srl, or at a Swiss multinational company (Novartis AG) or a German CRO (Aptuit srl, an Evotec company) based in Italy. To note, both Chiesi and Dompé belong to the so-called “Fab13”, (3) companies characterized by family control and a mission to keep a large part of their research and production in Italy, as well as their headquarters. Pleasingly, the publications covered a wide geographical distribution from Northern to Southern Italy, with 15 out of 20 Italian regions represented in the published research (Figure 1). The published work was distributed as follows: 40% of the publications featured corresponding authors affiliated with institutions in Northern Italy, followed by 36% and 24% of publications with corresponding authors working at institutions in Central and Southern Italy, respectively. These statistics are roughly in line with the demographic distribution within the Italian territory, whereby 46% of the population lives in Northern regions. To counteract depopulation and ensure a more homogeneous distribution of the funding, the National Recovery and Resilience Plan in 2021 (4)","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"5 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}