Han Yao, Yuanyuan Ren, Feng Wu, Longcai Cao, Jiadai Liu, Ming Yan, Xingshu Li
{"title":"The Discovery of a Novel AXL/Triple Angiokinase Inhibitor Based on 6-Chloro-Substituted Indolinone and Side Chain Methyl Substitution Inhibiting Pancreatic Cancer Growth and Metastasis","authors":"Han Yao, Yuanyuan Ren, Feng Wu, Longcai Cao, Jiadai Liu, Ming Yan, Xingshu Li","doi":"10.1021/acs.jmedchem.4c02130","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02130","url":null,"abstract":"In this study, we discovered and identified a novel AXL/triple angiokinase inhibitor <b>11b</b> by rational structural modification based on the structure of triple angiokinase inhibitor Nintedanib. We found that <b>11b</b> potently inhibited AXL expression with the IC<sub>50</sub> value of 3.75 nM and possessed similar inhibitory activity on KDR as Nintedanib. In the assay of antiproliferative activity on NIH/3T3, HUVEC, Bxpc-3, and MDA-MB-231, <b>11b</b> showed better inhibitory ability than Nintedanib. In pancreatic cancer xenograft mouse models from Bxpc-3 cells, even when the dosage was halved, <b>11b</b> exhibited better or comparable effects to Nintedanib (tumor growth inhibition (TGI) based on tumor volume change during the trial or tumor weight). Notably, we also found that <b>11b</b> prohibited Bxpc-3 resulted lung metastasis by inhibiting its epithelial–mesenchymal transition (EMT) process. Another mechanism assay also proved that <b>11b</b> inhibited the function of blood vessels and fibroblasts, promoted apoptosis of cancer and fibroblast cells, and exhibited low toxicity and good metabolic stability.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"53 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142874246","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}
Makafui Gasonoo, Soumitra Guin, José E. Teixeira, Edmund Oboh, Anusha Gokanapalle, Peter Miller, Jonathan Oliva, Francis M. Sverdrup, Christopher D. Huston, Marvin J. Meyers
{"title":"Discovery of an Orally Efficacious Pyrazolo[3,4-d]pyrimidine Benzoxaborole as a Potent Inhibitor of Cryptosporidium","authors":"Makafui Gasonoo, Soumitra Guin, José E. Teixeira, Edmund Oboh, Anusha Gokanapalle, Peter Miller, Jonathan Oliva, Francis M. Sverdrup, Christopher D. Huston, Marvin J. Meyers","doi":"10.1021/acs.jmedchem.4c02805","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02805","url":null,"abstract":"Cryptosporidiosis is a diarrheal disease caused by the parasite <i>Cryptosporidium</i> resulting in over 100,000 deaths annually. Here, we present a structure–activity relationship study of the benzoic acid position (R<sup>6</sup>) of pyrazolo[3,4-<i>d</i>]pyrimidine lead SLU-2815 (<b>1</b>), an inhibitor of parasite phosphodiesterase <i>Cp</i>PDE1, resulting in the discovery of benzoxaborole SLU-10906 (<b>63</b>) as a benzoic acid bioisostere. Benzoxaborole <b>63</b> is 10-fold more potent than <b>1</b> against the parasite in a cell-based infection model (EC<sub>50</sub> = 0.19 μM) and non-cytotoxic. Furthermore, <b>63</b> has a fast rate of parasite-killing and is orally efficacious in a <i>Cryptosporidium</i> mouse infection model (50 mg/kg BID), although relapse was observed 7 days post-drug treatment. The partial selectivity profile versus human phosphodiesterases is preserved with the benzoxaborole motif and represents an important feature to improve in future optimization. Benzoxaborole <b>63</b> represents an important advance toward the optimization of the pyrazolo[3,4-<i>d</i>]pyrimidine series and the identification of a drug to treat cryptosporidiosis.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"111 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142874305","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}
Zhe Nie, Roger Bonnert, Jet Tsien, Xiaoyi Deng, Christopher Higgs, Farah El Mazouni, Xiaoyu Zhang, Renzhe Li, Nhi Ho, Victoria Feher, Janet Paulsen, David M. Shackleford, Kasiram Katneni, Gong Chen, Alice C. F. Ng, Mitchell McInerney, Wen Wang, Jessica Saunders, Daniel Collins, Dandan Yan, Peng Li, Michael Campbell, Rahul Patil, Atanu Ghoshal, Pallab Mondal, Abhijit Kundu, Rajesh Chittimalla, Muralikumar Mahadeva, Sreekanth Kokkonda, John White, Rishi Das, Partha Mukherjee, Iñigo Angulo-Barturen, María Belén Jiménez-Díaz, Robert Malmstrom, Morgan Lawrenz, Agustina Rodriguez-Granillo, Pradipsinh K. Rathod, Diana R. Tomchick, Michael J. Palmer, Benoît Laleu, Tian Qin, Susan A. Charman, Margaret A. Phillips
{"title":"Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention","authors":"Zhe Nie, Roger Bonnert, Jet Tsien, Xiaoyi Deng, Christopher Higgs, Farah El Mazouni, Xiaoyu Zhang, Renzhe Li, Nhi Ho, Victoria Feher, Janet Paulsen, David M. Shackleford, Kasiram Katneni, Gong Chen, Alice C. F. Ng, Mitchell McInerney, Wen Wang, Jessica Saunders, Daniel Collins, Dandan Yan, Peng Li, Michael Campbell, Rahul Patil, Atanu Ghoshal, Pallab Mondal, Abhijit Kundu, Rajesh Chittimalla, Muralikumar Mahadeva, Sreekanth Kokkonda, John White, Rishi Das, Partha Mukherjee, Iñigo Angulo-Barturen, María Belén Jiménez-Díaz, Robert Malmstrom, Morgan Lawrenz, Agustina Rodriguez-Granillo, Pradipsinh K. Rathod, Diana R. Tomchick, Michael J. Palmer, Benoît Laleu, Tian Qin, Susan A. Charman, Margaret A. Phillips","doi":"10.1021/acs.jmedchem.4c02394","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02394","url":null,"abstract":"Malaria remains a serious global health challenge, yet treatment and control programs are threatened by drug resistance. Dihydroorotate dehydrogenase (DHODH) was clinically validated as a target for treatment and prevention of malaria through human studies with DSM265, but currently no drugs against this target are in clinical use. We used structure-based computational tools including free energy perturbation (FEP+) to discover highly ligand efficient, potent, and selective pyrazole-based <i>Plasmodium</i> DHODH inhibitors through a scaffold hop from a pyrrole-based series. Optimized pyrazole-based compounds were identified with low nM-to-pM <i>Plasmodium falciparum</i> cell potency and oral activity in a humanized SCID mouse malaria infection model. The lead compound DSM1465 is more potent and has improved absorption, distribution, metabolism and excretion/pharmacokinetic (ADME/PK) properties compared to DSM265 that support the potential for once-monthly chemoprevention at a low dose. This compound meets the objective of identifying compounds with potential to be used for monthly chemoprevention in Africa to support malaria elimination efforts.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"14 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142874242","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}
Alex G. Baldwin, David W. Foley, Ross Collins, Hyunah Lee, D. Heulyn Jones, Ben Wahab, Loren Waters, Josephine Pedder, Marie Paine, Gui Jie Feng, Lucia Privitera, Alexander Ashall-Kelly, Carys Thomas, Jason A. Gillespie, Lauramariú Schino, Delia Belelli, Cecilia Rocha, Gilles Maussion, Andrea I. Krahn, Thomas M. Durcan, Jonathan M. Elkins, Jeremy J. Lambert, John R. Atack, Simon E. Ward
{"title":"Discovery of MDI-114215: A Potent and Selective LIMK Inhibitor To Treat Fragile X Syndrome","authors":"Alex G. Baldwin, David W. Foley, Ross Collins, Hyunah Lee, D. Heulyn Jones, Ben Wahab, Loren Waters, Josephine Pedder, Marie Paine, Gui Jie Feng, Lucia Privitera, Alexander Ashall-Kelly, Carys Thomas, Jason A. Gillespie, Lauramariú Schino, Delia Belelli, Cecilia Rocha, Gilles Maussion, Andrea I. Krahn, Thomas M. Durcan, Jonathan M. Elkins, Jeremy J. Lambert, John R. Atack, Simon E. Ward","doi":"10.1021/acs.jmedchem.4c02694","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02694","url":null,"abstract":"LIMKs are serine/threonine and tyrosine kinases responsible for controlling cytoskeletal dynamics as key regulators of actin stability, ensuring synaptic health through normal synaptic bouton structure and function. However, LIMK1 overactivation results in abnormal dendritic synaptic development that characterizes the pathogenesis of Fragile X Syndrome (FXS). As a result, the development of LIMK inhibitors represents an emerging disease-modifying therapeutic approach for FXS. We report the discovery of MDI-114215 (<b>85</b>), a novel, potent allosteric dual-LIMK1/2 inhibitor that demonstrates exquisite kinome selectivity. <b>85</b> reduces phospho-cofilin in mouse brain slices and rescues impaired hippocampal long-term potentiation in brain slices from FXS mice. We also show that LIMK inhibitors are effective in reducing phospho-cofilin levels in iPSC neurons derived from FXS patients, demonstrating <b>85</b> to be a potential therapeutic candidate for FXS that could have broad application to neurological disorders or cancers caused by LIMK1/2 overactivation and actin instability.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"13 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142874306","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}
Yang Luo, Wenbin Jin, Jie Zang, Guochang Wang, Lin Zhu, Hank F. Kung
{"title":"Development of [68Ga]Ga/[177Lu]Lu-DOTA-NI-FAPI-04 Containing a Nitroimidazole Moiety as New FAPI Radiotracers with Improved Tumor Uptake and Retention","authors":"Yang Luo, Wenbin Jin, Jie Zang, Guochang Wang, Lin Zhu, Hank F. Kung","doi":"10.1021/acs.jmedchem.4c02015","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02015","url":null,"abstract":"Fibroblast activation protein (FAP), which is overexpressed in cancer-associated fibroblasts (CAFs), represents a promising target for cancer diagnosis and therapy. Hypoxia is a common feature of solid tumors. A bivalent agent, DOTA-NI-FAPI-04 (<b>1</b>), was developed by incorporating hypoxia-sensitive nitroimidazole (NI) into the FAP-targeting agent FAPI-04. Compound <b>1</b> exhibited a strong FAP binding affinity with an IC<sub>50</sub> of 7.44 nM. Radiolabeled [<sup>68</sup>Ga]Ga-<b>1</b> and [<sup>177</sup>Lu]Lu-<b>1</b> demonstrated enhanced <i>in vitro</i> cell uptake. <i>In vivo</i> positron emission tomography/computed tomography (PET/CT) imaging showed that [<sup>68</sup>Ga]Ga-<b>1</b> displayed significantly higher specific uptake and retention in U87MG tumor-bearing mice compared to [<sup>68</sup>Ga]Ga-FAPI-04 (SUV<sub>avg</sub>: 7.87 vs 1.99% ID/mL at 120 min). Biodistribution studies confirmed superior tumor uptake of [<sup>68</sup>Ga]Ga-<b>1</b> (48.15 vs 5.72% ID/g at 120 min). Similarly, [<sup>177</sup>Lu]Lu-<b>1</b> exhibited higher tumor uptake than [<sup>177</sup>Lu]Lu-FAPI-04 (50.75 vs 20.48% ID/g at 120 min). These preliminary results suggest that a nitroimidazole-containing bivalent-targeting agent, [<sup>68</sup>Ga]Ga/[<sup>177</sup>Lu]Lu-<b>1</b>, is a promising candidate for tumor theranostics.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"8 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142874304","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}
Timo Heinrich, Daniel Schwarz, Carl Petersson, Jakub Gunera, Sakshi Garg, Richard Schneider, Marina Keil, Lisa Grimmeisen, Andrea Unzue Lopez, Lisa Albers, Sarah Schlesiger, Alessia Gambardella, Joerg Bomke, Emma Carswell, Heike Schilke, Patrizia Diehl, Benjamin Doerfel, Djordje Musil, Elisabeth Trivier, Rebecca Broome, Sam Marshall, Alexander Balsiger, Erik Friedrich, Ana R. Lemos, Sandra P. Santos, Pedro M. F. Sousa, Filipe Freire, Tiago M. Bandeiras, Alessio Bortoluzzi, Dirk Wienke
{"title":"MoA Studies of the TEAD P-Site Binding Ligand MSC-4106 and Its Optimization to TEAD1-Selective Amide M3686","authors":"Timo Heinrich, Daniel Schwarz, Carl Petersson, Jakub Gunera, Sakshi Garg, Richard Schneider, Marina Keil, Lisa Grimmeisen, Andrea Unzue Lopez, Lisa Albers, Sarah Schlesiger, Alessia Gambardella, Joerg Bomke, Emma Carswell, Heike Schilke, Patrizia Diehl, Benjamin Doerfel, Djordje Musil, Elisabeth Trivier, Rebecca Broome, Sam Marshall, Alexander Balsiger, Erik Friedrich, Ana R. Lemos, Sandra P. Santos, Pedro M. F. Sousa, Filipe Freire, Tiago M. Bandeiras, Alessio Bortoluzzi, Dirk Wienke","doi":"10.1021/acs.jmedchem.4c01949","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01949","url":null,"abstract":"Taking the structural information into account, we were able to tune the TEAD selectivity for a specific chemotype. However, different TEAD selectivity profiles did not affect the compound potency or efficacy in the NCI-H226 viability assay. Amides based on <b>MSC-4106</b> or analogues showed improved viability efficacy compared with the corresponding acids. The amide <b>M3686</b> exhibited AUC-driven efficacy in NCI-H226 xenograft models and had an improved 25-fold lower human dose prediction than <b>MSC-4106</b>. <b>MSC-4106</b> was also used in HDX-MS studies to aid in the understanding of the MoA of P-site binding TEAD inhibitors. Artificial P-site binders rigidify certain areas in the periphery of the transcription factor that seem to be crucial for cofactor interaction, whereas a native fatty acid increased the protein dynamics of cofactor-binding interfaces.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"24 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858177","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}
Gwenaëlle Jézéquel, Zoé Grimanelli, Carole Guimard, Joëlle Bigay, Juliano Haddad, Jérôme Bignon, Cécile Apel, Vincent Steinmetz, Laurie Askenatzis, Hélène Levaïque, Clara Pradelli, Van Cuong Pham, Doan T. M. Huong, Marc Litaudon, Romain Gautier, Chaker El Kalamouni, Bruno Antonny, Sandy Desrat, Bruno Mesmin, Fanny Roussi
{"title":"Minimalist Natural ORPphilin Macarangin B Delineates OSBP Biological Function","authors":"Gwenaëlle Jézéquel, Zoé Grimanelli, Carole Guimard, Joëlle Bigay, Juliano Haddad, Jérôme Bignon, Cécile Apel, Vincent Steinmetz, Laurie Askenatzis, Hélène Levaïque, Clara Pradelli, Van Cuong Pham, Doan T. M. Huong, Marc Litaudon, Romain Gautier, Chaker El Kalamouni, Bruno Antonny, Sandy Desrat, Bruno Mesmin, Fanny Roussi","doi":"10.1021/acs.jmedchem.4c01705","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01705","url":null,"abstract":"OSBP ligands from the ORPphilin family are chemically complex natural products with promising anticancer properties. Here, we describe macarangin B, a natural racemic flavonoid selective for OSBP, which stands out from other ORPphilins due to its structural simplicity and distinct biological activity. Using a bioinspired strategy, we synthesized both (<i>R</i>,<i>R</i>,<i>R</i>) and (<i>S</i>,<i>S</i>,<i>S</i>)-macarangin B enantiomers, enabling us to study their interaction with OSBP based on their unique optical properties. Experimental and computational analyzes revealed that (<i>R</i>,<i>R</i>,<i>R</i>)-macarangin B has the highest affinity for OSBP. Importantly, both enantiomers showed significantly decreased cytotoxicity compared to other ORPphilins, suggesting OSBP is not the primary target in ORPphilin-induced cell death. Yet, OSBP is an attractive antiviral target, as it is hijacked by many positive-strand RNA viruses. Remarkably, (<i>R</i>,<i>R</i>,<i>R</i>)-macarangin B significantly inhibited Zika virus replication in human cells, highlighting its potential as a lead compound for antiviral drug development.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"103 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858176","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}
Qian Zhang, Wenhai Yin, Xinyao Chen, Aimin Zhou, Guixu Zhang, Zhi Zhao, Zhiqiang Li, Yan Zhang, Samuel Jacob Bunu, Jingshan Shen, Weiliang Zhu, Xiangrui Jiang, Zhijian Xu
{"title":"F-CPI: A Multimodal Deep Learning Approach for Predicting Compound Bioactivity Changes Induced by Fluorine Substitution","authors":"Qian Zhang, Wenhai Yin, Xinyao Chen, Aimin Zhou, Guixu Zhang, Zhi Zhao, Zhiqiang Li, Yan Zhang, Samuel Jacob Bunu, Jingshan Shen, Weiliang Zhu, Xiangrui Jiang, Zhijian Xu","doi":"10.1021/acs.jmedchem.4c02668","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02668","url":null,"abstract":"Fluorine (F) substitution is a common method of drug discovery and development. However, there are no accurate approaches available for predicting the bioactivity changes after F-substitution, as the effect of substitution on the interactions between compounds and proteins (CPI) remains a mystery. In this study, we constructed a data set with 111,168 pairs of fluorine-substituted and nonfluorine-substituted compounds. We developed a multimodal deep learning model (F-CPI). In comparison with traditional machine learning and popular CPI task models, the accuracy, precision, and recall of F-CPI (∼90, ∼79, and ∼45%) were higher than those of GraphDTA (∼86, ∼58, and ∼40%). The application of the F-CPI for the structural optimization of hit compounds against SARS-CoV-2 3CL<sup>pro</sup> by F-substitution achieved a more than 100-fold increase in bioactivity (IC<sub>50</sub>: 0.23 μM vs 28.19 μM). Therefore, the multimodal deep learning model F-CPI would be a veritable and effective tool in the context of drug discovery and design.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"11 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142867496","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}
Fangyuan Chen, Qingmei Liu, Lei Ma, Cuishi Yan, Haiman Zhang, Zhi Zhou, Wei Yi
{"title":"Identification of Novel Organo-Se BTSA-Based Derivatives as Potent, Reversible, and Selective PPARγ Covalent Modulators for Antidiabetic Drug Discovery","authors":"Fangyuan Chen, Qingmei Liu, Lei Ma, Cuishi Yan, Haiman Zhang, Zhi Zhou, Wei Yi","doi":"10.1021/acs.jmedchem.4c02803","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02803","url":null,"abstract":"Recent studies have identified selective peroxisome proliferator-activated receptor γ (PPARγ) modulators, which synergistically engage in the inhibition mechanism of PPARγ-Ser273 phosphorylation, as a promising approach for developing safer and more effective antidiabetic drugs. Herein, we present the design, synthesis, and evaluation of a new class of organo-Se compounds, namely, benzothiaselenazole-1-oxides (BTSAs), acting as potent, reversible, and selective PPARγ covalent modulators. Notably, <b>2n</b>, especially <b>(</b><i><b>R</b></i><b>)-2n</b>, displayed a high binding affinity and superior antidiabetic effects with diminished side effects. This is mainly because it can reversibly form a unique covalent bond with the Cys285 residue in PPARγ-LBD. Further mechanistic investigations revealed that it manifested such desired pharmacological profiles primarily by effectively suppressing PPARγ-Ser273 phosphorylation, enhancing glucose metabolism, and selectively upregulating the expression of insulin-sensitive genes. Collectively, our results suggest that <b>(</b><i><b>R</b></i><b>)-2n</b> holds promise as a lead compound for treating T2DM and also provides an innovative reversible covalent warhead reference for future covalent drug design.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"55 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858178","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 Biological Evaluation of 2-Arylaminopyrimidine Derivatives as Dual Cathepsin L and JAK Inhibitors for the Treatment of Acute Lung Injury","authors":"Chunwei Shen, Zhengtong Mao, Tianpeng Chen, Yingying Wei, Tao Zhou, Ningyuan Zhong, Gaoyang Zhu, Qiwen Shi, Zheyu Xie, Huajun Zhao, Xingxian Zhang","doi":"10.1021/acs.jmedchem.4c02030","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02030","url":null,"abstract":"Acute lung injury (ALI) is a disease characterized by pulmonary inflammation, blood barrier functional disorder, and hypoxemia. Herein, a series of 2-aminopyrimidine derivatives were synthesized. Most of them exhibited inhibitory effects on inflammatory cytokines IL-6 and IL-8 in human bronchial epithelial (HBE) cells at a concentration of 5 μM without significant cytotoxicity. Compound <b>A8</b> displayed an excellent anti-inflammatory activity, achieving inhibition rates of 83% for IL-6 and 85% for IL-8. Besides, <b>A8</b> has a strong binding affinity to CTSL and a good inhibitory activity on JAKs. Western blot analysis indicated that compound <b>A8</b> strongly blocked the maturation of CTSL and the phosphorylation of p-38, p-65, and STATs, thereby repressing the activation of the MAPK, NF-κB, and JAK/STAT signaling pathway. Moreover, animal experiments showed that <b>A8</b> played a protective and therapeutic role in ALI in mice, validating its potential as a treatment for ALI.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"31 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849172","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}
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