Journal of Medicinal Chemistry最新文献

{"title":"Target Ligand Separation and Identification of Isoforsythiaside as a Histone Lysine-Specific Demethylase 1 Covalent Inhibitor Against Breast Cancer Metastasis","authors":"Mengzhen Gu, Xiaoqing Xu, Xiaoping Wang, Yun Wang, Yu Zhao, Xiaoxian Hu, Lu Zhu, Zhenzhong Deng, Chao Han","doi":"10.1021/acs.jmedchem.4c02277","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02277","url":null,"abstract":"Histone lysine-specific demethylase 1 (LSD1) is hyperactive in breast cancer, which is associated with the metastasis of the tumor. Current irreversible LSD1 inhibitors are all synthesized by covalently binding to the flavin adenine dinucleotide cofactor, which often have side effects due to the high affinity for a variety of targets. Here, we identified isoforsythiaside (IFA), a natural phenylpropanoid glycoside isolated from <i>Forsythia suspensa</i>, as a novel covalent inhibitor of LSD1. The target ligand fishing technique and LC–MS/MS analysis identified that IFA could covalently bind to the Ser817 residue of LSD1 by α,β-unsaturated ketone moiety to block the amine oxidase-like domain of LSD1. Moreover, RBMS3/Twist1/MMP2, the downstream signaling pathway of LSD1, was activated after IFA treatment to inhibit the metastasis of MDA-MB-231 cells <i>in vitro</i> and <i>in vivo</i>. This study provided novel molecular templates for development of LSD1 covalence-binding inhibitor and laid a foundation for developing agents against breast carcinoma metastasis for targeting LSD1.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580385","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":"A Target Class Ligandability Evaluation of WD40 Repeat-Containing Proteins.","authors":"Suzanne Ackloo, Fengling Li, Magda Szewczyk, Almagul Seitova, Peter Loppnau, Hong Zeng, Jin Xu, Shabbir Ahmad, Yelena A Arnautova, A J Baghaie, Serap Beldar, Albina Bolotokova, Paolo A Centrella, Irene Chau, Matthew A Clark, John W Cuozzo, Saba Dehghani-Tafti, Jeremy S Disch, Aiping Dong, Antoine Dumas, Jianwen A Feng, Pegah Ghiabi, Elisa Gibson, Justin Gilmer, Brian Goldman, Stuart R Green, Marie-Aude Guié, John P Guilinger, Nathan Harms, Oleksandra Herasymenko, Scott Houliston, Ashley Hutchinson, Steven Kearnes, Anthony D Keefe, Serah W Kimani, Trevor Kramer, Maria Kutera, Haejin A Kwak, Cristina Lento, Yanjun Li, Jenny Liu, Joachim Loup, Raquel A C Machado, Christopher J Mulhern, Sumera Perveen, Germanna L Righetto, Patrick Riley, Suman Shrestha, Eric A Sigel, Madhushika Silva, Michael D Sintchak, Belinda L Slakman, Rhys D Taylor, James Thompson, Wen Torng, Carl Underkoffler, Moritz von Rechenberg, Ryan T Walsh, Ian Watson, Derek J Wilson, Esther Wolf, Manisha Yadav, Aliakbar K Yazdi, Junyi Zhang, Ying Zhang, Vijayaratnam Santhakumar, Aled M Edwards, Dalia Barsyte-Lovejoy, Matthieu Schapira, Peter J Brown, Levon Halabelian, Cheryl H Arrowsmith","doi":"10.1021/acs.jmedchem.4c02010","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02010","url":null,"abstract":"<p><p>Target class-focused drug discovery has a strong track record in pharmaceutical research, yet public domain data indicate that many members of protein families remain unliganded. Here we present a systematic approach to scale up the discovery and characterization of small molecule ligands for the WD40 repeat (WDR) protein family. We developed a comprehensive suite of protocols for protein production, crystallography, and biophysical, biochemical, and cellular assays. A pilot hit-finding campaign using DNA-encoded chemical library selection followed by machine learning (DEL-ML) to predict ligands from virtual libraries yielded first-in-class, drug-like ligands for 7 of the 16 WDR domains screened, thus demonstrating the broader ligandability of WDRs. This study establishes a template for evaluation of protein family wide ligandability and provides an extensive resource of WDR protein biochemical and chemical tools, knowledge, and protocols to discover potential therapeutics for this highly disease-relevant, but underexplored target class.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566387","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":"Azobenzene-Tagged Photopeptides Exhibiting Excellent Selectivity and Light-Induced Cytotoxicity in MCF-7 Cells over HeLa and A549","authors":"Sambit Pradhan, Surajit Sarker, Pakkirisamy Thilagar","doi":"10.1021/acs.jmedchem.4c01113","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01113","url":null,"abstract":"The precise regulation of proteasome activity has become a focal point in current research, particularly its implications in cancer treatment. Bortezomib is used for treating multiple myeloma and is found to be ineffective against solid tumors. A spatiotemporal control over the proteasome is one of the solutions to resolve these issues using external stimuli, such as light. Thus, we designed and synthesized azobenzene-containing tripeptide vinyl sulfones <b>1</b>, <b>2</b>, <b>3</b>, and <b>4</b>, as the azobenzene moiety can impart E↔Z isomerism upon exposure to UV light. Further, the hydrophobicity of these peptides was fine-tuned by systematically varying the size of hydrophobic amino acids at the P1, P2, and P3 positions. The light-induced Z isomers of these photopeptides showed excellent cellular potency in HeLa, MCF-7, and A549 cell lines. Photopeptide <b>4</b> with valine at the proximal position, phenylalanine at P2, and leucine at the P1 positions exhibited 19.3- and 6.6-fold cellular potency in MCF-7 and A549 cells, respectively.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563316","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":"Designing Quasi-Intrinsic Photosensitizers with Dual Function of Fluorescence Imaging and Photodynamic Therapy","authors":"Xixi Cui, Jianzhong Fan, Yang Gao, Xucong Zhou, Changzhe Zhang, Qingtian Meng","doi":"10.1021/acs.jmedchem.4c02213","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02213","url":null,"abstract":"Photosensitizers (PSs) with effective two-photon absorption in the therapeutic window are the key to two-photon photodynamic therapy. However, the traditional exogenous PSs usually lead to rejection in the body. Besides, the precise visualization of treatments proposes new demands and challenges for the design of PSs. Accordingly, in this work, a series of quasi-intrinsic PSs are obtained based on the artificial base 2-amino-8-(1′-β-<span>d</span>-2′-deoxyribofuranosyl)-imidazo[1,2-α]-1,3,5-triazin-4(8<i>H</i>)-one (P). The calculations show that the structural modification could enhance the two-photon absorption and fluorescence emission, which is beneficial for tumor localization. Furthermore, the reduced singlet–triplet energy gaps and enhanced spin–orbit coupling contribute to the rapid intersystem crossing process, which results in a triplet state with high quantum yields. To ensure the phototherapeutic performance of the newly designed PSs, we also examined the vertical electron affinity and vertical ionization potential for generation of superoxide anions, as well as the T₁ energy required to produce singlet oxygen.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562189","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":"Targeting Periplakin of Novel Benzenesulfonamides as Highly Selective Agonists for the Treatment of Vitiligo","authors":"Hui Zhong, Panpan Li, Qiuming Yan, Yu Xia, Xin Zhang, Yifan Lai, Liqiang Li, Feifei Wang, Jing Shang, Xiaoming Zha","doi":"10.1021/acs.jmedchem.4c01717","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01717","url":null,"abstract":"Vitiligo is the most common cause of depigmentation worldwide, with immunosuppressive treatments often being inefficient and prone to recurrence, making it essential to identify new therapeutic targets. Periplakin (PPL) has been identified and confirmed as a key factor in vitiligo-related depigmentation. Based on this, a series of selective PPL agonists, specifically benzenesulfonamides, have been developed. Among these, compound <b>I-3</b> exhibits superior efficacy compared to ruxolitinib, the only FDA-approved treatment for vitiligo. <b>I-3</b> has been shown to increase cAMP levels by regulating PPL, which enhances MITF expression, a key transcription factor in melanin biosynthesis. Additionally, <b>I-3</b> promotes melanin production by regulating tryptophan metabolism. In summary, PPL is a promising drug target, and <b>I-3</b> has strong potential for future treatment of vitiligo due to its high selectivity and favorable druggability.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562187","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":"Synthesis and Biological Evaluation of New Chalcogen Semicarbazone (S, Se) and Their Azole Derivatives against Chagas Disease","authors":"Mercedes Rubio-Hernández, Verónica Alcolea, Elany Barbosa da Silva, Miriam A. Giardini, Thaís H. M Fernandes, Nuria Martínez-Sáez, Anthony J. O’Donoghue, Jair L. Siqueira-Neto, Silvia Pérez-Silanes","doi":"10.1021/acs.jmedchem.4c01535","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01535","url":null,"abstract":"Chagas disease is caused by the eukaryote parasite <i>Trypanosoma cruzi</i>. Current treatment exhibits limited efficacy and selenium-based compounds emerged as promising candidates for new therapies which is surpassing its bioisoster, sulfur. We designed new thiosemicarbazones, thiazoles, selenosemicarbazones and selenazoles, using isosteric substitution. We synthesized 57 new chalcogen compounds which were evaluated against <i>T. cruzi</i>, C2C12 cells and cruzain, the main target of this parasite. Additionally, human cathepsin L, was tested for selectivity. Three compounds were selected, based on their activity against the intracellular amastigotes (EC₅₀ &lt; 1 μM, SI &gt; 10) and cruzain (IC₅₀ &lt; 100 nM, SI &gt; 5.55) which compared favorably with the approved drug, Benznidazole, and the well-established cruzain inhibitor K777. Seleno-compounds demonstrated enhanced activity and selenazoles showed a decrease in selenium-associated toxicity. Compound 4-methyl-2-(2-(1-(3-nitrophenyl)ethylidene)hydrazineyl)-1,3-selenazole (<i><b>Se</b></i><b>2h</b>) emerged as a promising candidate, and its binding to cruzain was investigated. Pharmacokinetic assessment was conducted, showing a favorable profile for subsequent <i>in vivo</i> assays.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562188","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 Activity Evaluation of BRD4 PROTAC Based on Alkenyl Oxindole-DCAF11 Pair","authors":"Man Zhao, Wenjing Ma, Jinyi Liang, Yubao Xie, Tianzi Wei, Ming Zhang, Jiajie Qin, Lingyin Lao, Ruilin Tian, Haiqiang Wu, Jin Cheng, Min Li, Yuyang Liu, Liang Hong, Guofeng Li","doi":"10.1021/acs.jmedchem.4c01767","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01767","url":null,"abstract":"Proteolytic targeting chimera (PROTAC) represent an advanced strategy for targeting undruggable proteins, and the molecular warheads targeting E3 ligases play a crucial role. Recently, we explored an alkenyl oxindole warhead targeting the E3 ligase DCAF11 and sought to validate its potential. In this study, we synthesized a range of BRD4 PROTACs (<b>8a</b>–<b>8o</b>, <b>14a–14f</b>, <b>22a–22m</b>) with modified alkenyl oxindole warheads and developed a high-throughput screening system based on high-content imaging. We identified <b>L134</b> (<b>22a</b>) as a potent BRD4 degrader, achieving BRD4 degradation (<i>D</i>_max &gt; 98%, DC₅₀ = 7.36 nM) and demonstrating antitumor activity. Mechanically, BRD4 degradation by <b>L134</b> was mediated through the ubiquitin-proteasome system in a DCAF11-dependent manner. Therefore, this study provides a rapid screening method for effective PROTACs and highlights the PROTAC <b>L134</b> based on alkenyl oxindole-DCAF11 pair as a promising candidate for treating BRD4-driven cancers.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541953","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":"Antibacterial, Antibiofilm, and Anti-inflammatory Effects of a Novel Thrombin-Derived Peptide in Sepsis Models: Insights into Underlying Mechanisms","authors":"S. Dinesh Kumar, Jin Kyeong Lee, Naveen Kumar Radhakrishnan, Jeong Kyu Bang, Byeongkwon Kim, Shubhash Chandra Chaudhary, Ajish Chelladurai, Byambasuren Ganbaatar, Eun Young Kim, Chul Won Lee, Sungtae Yang, Yangmee Kim, Song Yub Shin","doi":"10.1021/acs.jmedchem.4c02157","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02157","url":null,"abstract":"We developed two short helical antimicrobial peptides, HVF18-a3 and its <span>d</span>-enantiomer, HVF18-a3-d, derived from the thrombin C-terminal peptide HVF18. These peptides exhibit potent antimicrobial activity against various bacteria by compromising both the outer and inner membranes, with low hemolytic activity. They are stable in the presence of physiological salts and human serum, exhibiting a low potential for developing drug resistance and excellent antibiofilm activity against Gram-negative bacteria. HVF18-a3-d also neutralized lipopolysaccharide (LPS) through direct binding interactions and suppressed the production of inflammatory cytokines through the inflammatory signaling pathway mediated by Toll-like receptor 4 in RAW264.7 cells stimulated with LPS. Both pre- and post-treatment with HVF18-a3-d significantly protected mice against fatal septic shock induced by carbapenem resistant <i>Acinetobacter baumannii</i>. These findings suggest HVF18-a3 and HVF18-a3-d are promising candidates for developing antibiotics against Gram-negative sepsis.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541949","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":"DBPR116, a Prodrug of BPRMU191, in Combination with Naltrexone as a Safer Opioid Analgesic Than Morphine via Peripheral Administration","authors":"Shu-Yu Lin, Yung-Chiao Chang, Ya-Wen Tien, Yu-Hsien Kuo, Hsiao-Fu Chang, Li-Chin Ou, Ya-Ping Chen, Kuei-Hua Chang, Ying-Ting Hsu, Yu-Chen Huang, Chen-Ming Yang, Ping-Yee Law, Jing-Hua Xi, Pao-Luh Tao, Horace H. Loh, Teng-Kuang Yeh, Hong Zhuang, Hsing-Pang Hsieh, Chuan Shih, Chiung-Tong Chen, Shiu-Hwa Yeh, Shau-Hua Ueng","doi":"10.1021/acs.jmedchem.4c02107","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02107","url":null,"abstract":"The development of opioid analgesics with reduced adverse effects is an unmet need. In a previous study, we discovered a unique combination of BPRMU191 and morphinan antagonists that produced potent antinociception with reduced adverse effects after central administration (intrathecal or intracerebroventricular). BPRMU191/naltrexone exhibits notable <i>in vitro</i> and <i>in vivo</i> pharmacological properties. However, the poor blood–brain barrier penetrative ability of BPRMU191 restricts its clinical application. In this study, we utilized a prodrug strategy to deliver sufficient brain concentrations of BPRMU191 and selected compound <b>2</b> (DBPR116) with the best physicochemical and pharmacological properties among other <i>in vivo</i> active prodrugs. The <i>in vivo</i> pharmacological studies of compound <b>2</b>/naltrexone, including thermally stimulated pain, cancer pain, constipation, sedation, psychological dependence, heart rate, and respiratory frequency measurements, demonstrated that it was a safer opioid analgesic than morphine in pain control.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541950","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":"NGT: Generative AI with Synthesizability Guarantees Discovers MC2R Inhibitors from a Tera-Scale Virtual Screen","authors":"Saulo H. P de Oliveira, Aryan Pedawi, Victor Kenyon, Henry van den Bedem","doi":"10.1021/acs.jmedchem.4c01763","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01763","url":null,"abstract":"Commercially available, synthesis-on-demand virtual libraries contain upward of trillions of readily synthesizable compounds for drug discovery campaigns. These libraries are a critical resource for rapid cycles of in silico discovery, property optimization and in vitro validation. However, as these libraries continue to grow exponentially in size, traditional search strategies encounter significant limitations. Here we present NeuralGenThesis (NGT), an efficient reinforcement learning approach to generate compounds from ultralarge libraries that satisfy user-specified constraints. Our method first trains a generative model over a virtual library and subsequently trains a normalizing flow to learn a distribution over latent space that decodes constraint-satisfying compounds. NGT allows multiple constraints simultaneously without dictating how molecular properties are calculated. Using NGT, we generated potent and selective inhibitors for the melanocortin-2 receptor (MC2R) from a three trillion compound library. NGT offers a powerful and scalable solution for navigating ultralarge virtual libraries, accelerating drug discovery efforts.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142536942","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}