Journal of Medicinal Chemistry最新文献_第3页

Discovery of GJG057, a Potent and Highly Selective Inhibitor of Leukotriene C4 Synthase

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-02-17 DOI: 10.1021/acs.jmedchem.4c02897

Gebhard Thoma, Wolfgang Miltz, Rudolf Waelchli, David Orain, Carsten Spanka, Odile Decoret, Romain M. Wolf, Brian Hurley, Atwood K. Cheung, David A. Sandham, Ayako Honda, Ritesh Tichkule, Xin Chen, Tajesh Patel, Nancy Labbe-Giguere, Kian L. Tan, Clayton Springer, John Manchester, Andrew J. Culshaw, Peter Hunt, Honnappa Srinivas, Carlos A. Penno, Sandrine Ferrand, Shin Numao, Ulrich Schopfer, Petra Jäger, Nathalie Wack, Franziska Hasler, Beatrice Urban, Miriam Sindelar, Pius Loetscher, Michael Kiffe, Xiaojun Ren, Paul Nicklin, Kevin White, Khaushik Subramanian, Haoyuan Liu, Ellena J. Growcott, Till A. Röhn

{"title":"Discovery of GJG057, a Potent and Highly Selective Inhibitor of Leukotriene C4 Synthase","authors":"Gebhard Thoma, Wolfgang Miltz, Rudolf Waelchli, David Orain, Carsten Spanka, Odile Decoret, Romain M. Wolf, Brian Hurley, Atwood K. Cheung, David A. Sandham, Ayako Honda, Ritesh Tichkule, Xin Chen, Tajesh Patel, Nancy Labbe-Giguere, Kian L. Tan, Clayton Springer, John Manchester, Andrew J. Culshaw, Peter Hunt, Honnappa Srinivas, Carlos A. Penno, Sandrine Ferrand, Shin Numao, Ulrich Schopfer, Petra Jäger, Nathalie Wack, Franziska Hasler, Beatrice Urban, Miriam Sindelar, Pius Loetscher, Michael Kiffe, Xiaojun Ren, Paul Nicklin, Kevin White, Khaushik Subramanian, Haoyuan Liu, Ellena J. Growcott, Till A. Röhn","doi":"10.1021/acs.jmedchem.4c02897","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02897","url":null,"abstract":"Leukotriene C4 synthase (LTC4S) is a glutathione S-transferase that mediates the biosynthesis of cysteinyl leukotriene C4 (LTC4). Cysteinyl leukotrienes (CysLTs) are lipid mediators that drive type 2 inflammation, bronchoconstriction, and itch. Thus, LTC4S represents an attractive drug target for the treatment of allergic inflammatory diseases, but to date, no LTC4S inhibitor has been tested in patients. Herein, we disclose the discovery and preclinical profiling of the highly selective, oral LTC4S inhibitor GJG057 (compound 1), which exhibits 20-fold improved potency (IC50 = 44 nM) versus clinical candidate AZD9898 (IC50 = 900 nM) in a human whole blood LTC4 release assay. GJG057 showed efficacy in a murine asthma exacerbation model as well as in a mastoparan-induced skin challenge PK/PD model and was profiled in GLP toxicology studies. Despite its promising properties, GJG057 was not progressed into clinical trials as an oral drug. Its potential as a topical drug is currently being evaluated.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"24 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427366","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}

引用次数: 0

Design, Synthesis, and Characterization of GluN2A Negative Allosteric Modulators Suitable for In Vivo Exploration

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-02-17 DOI: 10.1021/acs.jmedchem.4c02751

François P. Bischoff, Sven Van Brandt, Marcel Viellevoye, Michel De Cleyn, Michel Surkyn, Rodrigo J. Carbajo, Maria Dominguez Blanco, Berthold Wroblowski, Nathan K. Karpowich, Ruth A. Steele, Celine Schalk-Hihi, Robyn Miller, David Duda, Paul Shaffer, Scott Ballentine, Sirak Simavorian, Brian Lord, Robert A. Neff, Pascal Bonaventure, Harrie J. M. Gijsen

{"title":"Design, Synthesis, and Characterization of GluN2A Negative Allosteric Modulators Suitable for In Vivo Exploration","authors":"François P. Bischoff, Sven Van Brandt, Marcel Viellevoye, Michel De Cleyn, Michel Surkyn, Rodrigo J. Carbajo, Maria Dominguez Blanco, Berthold Wroblowski, Nathan K. Karpowich, Ruth A. Steele, Celine Schalk-Hihi, Robyn Miller, David Duda, Paul Shaffer, Scott Ballentine, Sirak Simavorian, Brian Lord, Robert A. Neff, Pascal Bonaventure, Harrie J. M. Gijsen","doi":"10.1021/acs.jmedchem.4c02751","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02751","url":null,"abstract":"N-Methyl-d-aspartate receptors are ionotropic glutamate receptors that mediate fast excitatory neurotransmission in the central nervous system. These receptors play essential roles in synaptic plasticity, learning, and memory and are implicated in various neuropathological and psychiatric disorders. Selective modulation of NMDAR subtypes, particularly GluN2A, has proven challenging. The TCN-201 derivatives MPX-004 and MPX-007 are potent and selective for GluN2A receptors, yet their physical properties limit their in vivo utility. In this study, we optimized the MPX-004/MPX-007 scaffold by modifying the linker region between the distal halogenated aromatic ring and the central pyrazine nucleus, resulting in the identification of potent and selective compounds with improved drug-like properties. Notably, compound 1 was used to develop the first GluN2A NAM-based radioligand, and compound 11 showed improved pharmacokinetics and dose-dependent receptor occupancy in vivo. Thus, we provide an array of powerful new tools for the study of GluN2A receptors.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"10 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427367","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}

引用次数: 0

Design, Synthesis, and Biological Evaluation of BODIPY-Caged Resiquimod as a Dual-Acting Phototherapeutic

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-02-17 DOI: 10.1021/acs.jmedchem.4c02606

Eslam Roshdy, Haruto Taniguchi, Yoki Nakamura, Haruko Takahashi, Yutaka Kikuchi, Ismail Celik, Elsayed S. I. Mohammed, Yasuhiro Ishihara, Norimitsu Morioka, Manabu Abe

{"title":"Design, Synthesis, and Biological Evaluation of BODIPY-Caged Resiquimod as a Dual-Acting Phototherapeutic","authors":"Eslam Roshdy, Haruto Taniguchi, Yoki Nakamura, Haruko Takahashi, Yutaka Kikuchi, Ismail Celik, Elsayed S. I. Mohammed, Yasuhiro Ishihara, Norimitsu Morioka, Manabu Abe","doi":"10.1021/acs.jmedchem.4c02606","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02606","url":null,"abstract":"Resiquimod, an imidazoquinoline scaffold, exhibits potent immunotherapeutic activity but is associated with off-target effects, limiting its clinical utility. To address this limitation, we developed a novel BODIPY-caged resiquimod that is responsive to red light, combining photocaging and photodynamic therapy functionalities. Molecular docking studies guided identification of the optimal caging site for resiquimod, effectively masking its immune activity. BODIPY-caged resiquimod remained inactive under dark conditions, effectively masking resiquimod’s immunostimulatory effects. However, red light irradiation precisely uncaged resiquimod, inducing robust immune activation, even in the presence of N-acetyl cysteine as an antioxidant. Notably, the attachment of resiquimod to BODIPY reduced the dark toxicity typically associated with BODIPY as a photosensitizer. In 3D spheroid models of HeLa and A549 cells, BODIPY-caged resiquimod demonstrated spatiotemporal control over cytotoxicity, significantly enhancing cell death only upon irradiation. This dual-function therapeutic approach highlights a “win–win” strategy: precise, red-light-mediated control of immune activation and photodynamic efficacy with reduced collateral toxicity.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"64 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427251","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}

引用次数: 0

Impact of Fluorine Pattern on Lipophilicity and Acid–Base Properties of 2-(Thiofluoroalkyl)pyridines: Insights from Experiments and Statistical Modeling

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-02-17 DOI: 10.1021/acs.jmedchem.4c03045

Miguel Bernús, Gonzalo D. Núñez, Will C. Hartley, Marc Guasch, Jordi Mestre, Maria Besora, Jorge J. Carbó, Omar Boutureira

{"title":"Impact of Fluorine Pattern on Lipophilicity and Acid–Base Properties of 2-(Thiofluoroalkyl)pyridines: Insights from Experiments and Statistical Modeling","authors":"Miguel Bernús, Gonzalo D. Núñez, Will C. Hartley, Marc Guasch, Jordi Mestre, Maria Besora, Jorge J. Carbó, Omar Boutureira","doi":"10.1021/acs.jmedchem.4c03045","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03045","url":null,"abstract":"Lipophilicity and acid–base properties are two key aspects of the optimization of a compound in drug discovery. Using 19F NMR, we experimentally determined the log D7.4 of a wide array of 2-thiofluoroalkyl (SRF) and 2-sulfonyl fluoroalkyl (SO2RF) substituted pyridines and the pKa values of their protonated counterparts. Statistical modeling based on constitutional and DFT descriptors provided further insights into the structure–property relationship, explaining the experimental observations and predicting log D7.4 values. Our results highlight the influence of fluorination topology in SRF fragments and demonstrate the dual effect of fluorine on molecular polarity, increasing the hydrophobic surface and the polarity of the sulfur moiety. By analyzing methyl- and ethyl-derived fragments, we found a gradient in log D7.4 values influenced by the oxidation state of the sulfur atom and fluorination pattern. Our findings emphasize the context-dependent impact of fluorination and offer insights to better understand the impact of thiofluoroalkyl chains on these physicochemical properties.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"180 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427278","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}

引用次数: 0

Design, Synthesis, and Mechanism Study of Novel BMX Inhibitors Based on the Core of 1,3,5-Triazin-2-Amine for the Treatment of Gastric Carcinoma

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-02-15 DOI: 10.1021/acs.jmedchem.4c01947

Nan Wang, Xianxia Zeng, Mengyang Xu, Yamin Shi, Jie Zhang, Zhen Ling, Xin Xie, Tingsheng Qin, Huaizheng Huang, Jie Yang, Ting Ma, Linhong He

{"title":"Design, Synthesis, and Mechanism Study of Novel BMX Inhibitors Based on the Core of 1,3,5-Triazin-2-Amine for the Treatment of Gastric Carcinoma","authors":"Nan Wang, Xianxia Zeng, Mengyang Xu, Yamin Shi, Jie Zhang, Zhen Ling, Xin Xie, Tingsheng Qin, Huaizheng Huang, Jie Yang, Ting Ma, Linhong He","doi":"10.1021/acs.jmedchem.4c01947","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01947","url":null,"abstract":"BMX, a member of the Tec family of kinases, plays a pivotal role in the occurrence and progression of cancers and multiple chronic inflammations. However, there are rarely BMX inhibitors reported, and the signaling pathways mediated by BMX are still poorly understood. In this study, a series of novel BMX inhibitors bearing the core of 1,3,5-triazin-2-amine were designed and synthesized by structural modifications from the lead compound B1c. Among them, compound B6a irreversibly and selectively inhibited BMX (IC50 = 12 nM) and displayed good antiproliferative activities in various cancer cell lines. A mechanism study in gastric carcinoma HGC-27 and MGC-803 cells revealed that B6a promoted cell cycle arrest and apoptosis, triggered protective autophagy, and suppressed the BMX/AKT/mTOR pathway. Notably, although B6a’s bioavailability was extremely low, it still exhibited excellent antitumor potency in the HGC-27 xenograft model with high safety, demonstrating that B6a was a promising BMX inhibitor and worth further exploration.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"48 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143418191","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}

引用次数: 0

Dissecting Structural Requirements of Leucinostatin A Derivatives for Antiprotozoal Activity and Mammalian Toxicity

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-02-14 DOI: 10.1021/acs.jmedchem.4c01989

Lukas Rimle, Dimanthi Pliatsika, Noëlle Arnold, Sandra Kurth, Marcel Kaiser, Pascal Mäser, Michael Kemmler, Michael Adams, Rainer Riedl, Christoph von Ballmoos

{"title":"Dissecting Structural Requirements of Leucinostatin A Derivatives for Antiprotozoal Activity and Mammalian Toxicity","authors":"Lukas Rimle, Dimanthi Pliatsika, Noëlle Arnold, Sandra Kurth, Marcel Kaiser, Pascal Mäser, Michael Kemmler, Michael Adams, Rainer Riedl, Christoph von Ballmoos","doi":"10.1021/acs.jmedchem.4c01989","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01989","url":null,"abstract":"Lefleuganan, a clinical stage drug candidate for the treatment of cutaneous leishmaniasis, is a synthetic nonapeptide inspired by the natural antimicrobial peptide leucinostatin A, exhibiting excellent antiprotozoal activity in the low nM range. Lefleuganan shows strongly reduced acute toxicity, making it amenable for clinical use. Here, using a broad set of in vivo and in vitro measurements using purified enzymes, we find that leucinostatin A, but not lefleuganan, specifically targets the mitochondrial ATP synthase, inhibiting ATP synthesis by the human, bovine, and yeast enzyme in the nanomolar range. In a structure–activity relationship study covering the chemical space between the two compounds, hydroxyleucine at position 7 in leucinostatin A is identified as the key responsible moiety for specific ATP synthase inhibition and systemic toxicity. Our data suggest that efficient antiprotozoal activity of these class of compounds is mediated by efficient energetic uncoupling of negatively charged membranes.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"64 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143418341","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}

引用次数: 0

Discovery of Novel Isoxazole-Based Small-Molecule Toll-Like Receptor 8 Antagonists.

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-02-14 DOI: 10.1021/acs.jmedchem.4c03148

Troy Matziol, Valerij Talagayev, Tjaša Slokan, Nika Strašek Benedik, Janine Holze, Matej Sova, Gerhard Wolber, Günther Weindl

{"title":"Discovery of Novel Isoxazole-Based Small-Molecule Toll-Like Receptor 8 Antagonists.","authors":"Troy Matziol, Valerij Talagayev, Tjaša Slokan, Nika Strašek Benedik, Janine Holze, Matej Sova, Gerhard Wolber, Günther Weindl","doi":"10.1021/acs.jmedchem.4c03148","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03148","url":null,"abstract":"Toll-like receptor 8 (TLR8) recognizes viral and bacterial RNA, initiating inflammatory responses that are crucial for innate immunity. Dysregulated TLR8 signaling contributes to autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis, driving chronic inflammation and tissue damage. Therefore, targeting TLR8 has gained attention as a promising therapeutic strategy. We report a novel selective TLR8 antagonist scaffold identified through computational modeling and simulation. In silico-guided rational drug design and synthesis led to potent isoxazole-based compounds that were characterized by structure-activity relationships. The most active compounds inhibited TLR8-mediated signaling in cell lines and primary cells, reduced MyD88 recruitment, suppressed NF-κB- and IRF-dependent signaling, and decreased inflammatory responses. In silico and pharmacological analyses demonstrated competitive binding to the pocket of chemical ligands within the TLR8 dimerization interface. These highly selective and potent TLR8 antagonists possess favorable physicochemical properties, representing potential clinical candidates for TLR8-targeted therapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412366","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}

引用次数: 0

Discovery of Novel Aromatic Urea-Imidazole Salt Derivatives for Cancer Therapy via Targeting ERK1/2.

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-02-14 DOI: 10.1021/acs.jmedchem.4c01434

Mengqi Wang, Shuping Yang, Xinge Li, Yingying Zheng, Yan Bai, Wenhan Luo, Gongming Zhu, Junbiao Chang, Bo Zhu

{"title":"Discovery of Novel Aromatic Urea-Imidazole Salt Derivatives for Cancer Therapy via Targeting ERK1/2.","authors":"Mengqi Wang, Shuping Yang, Xinge Li, Yingying Zheng, Yan Bai, Wenhan Luo, Gongming Zhu, Junbiao Chang, Bo Zhu","doi":"10.1021/acs.jmedchem.4c01434","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01434","url":null,"abstract":"Extracellular signal-regulated kinases (ERKs) are pivotal signaling molecules in the RAS-RAF-MEK-ERK signaling pathway and have emerged as potential antitumor targets, providing a promising strategy for tumor therapy. Therefore, the development of antitumor drugs targeting ERK protein has received extensive attention. Here, we developed a compound library based on a series of novel aromatic urea-imidazole salt derivatives and conducted phenotypic screening against various cancer cell lines. Notably, 21y exhibited high efficacy against MCF-7 cells (IC50 = 0.67 μM). Furthermore, label-free drug affinity responsive target stability (DARTS) and LC-MS/MS proteomics techniques revealed that 21y directly targets ERK1/2. Mechanistically, 21y induced cell apoptosis and autophagy-related cell death. In vivo studies confirmed that 21y strongly inhibited tumor growth and lung metastasis in breast cancer. Taken together, 21y targets ERK1/2 as a promising therapeutic agent for breast cancer therapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412365","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}

引用次数: 0

Discovery of Pyrrolopyrazine Carboxamide Derivatives as Potent and Selective FGFR2/3 Inhibitors that Overcome Mutant Resistance.

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-02-13 Epub Date: 2025-01-31 DOI: 10.1021/acs.jmedchem.4c03205

Yazhou Wang, Yihong Zhang, Jinxin Liu, Jichen Zhao, Chao Wang, Fanye Meng, Xin Cai, Man Zhang, Alex Aliper, Tao Liang, Feng Yan, Feng Ren, Jiong Lan, Qiang Lu, Fusheng Zhou, Alex Zhavoronkov, Xiao Ding

{"title":"Discovery of Pyrrolopyrazine Carboxamide Derivatives as Potent and Selective FGFR2/3 Inhibitors that Overcome Mutant Resistance.","authors":"Yazhou Wang, Yihong Zhang, Jinxin Liu, Jichen Zhao, Chao Wang, Fanye Meng, Xin Cai, Man Zhang, Alex Aliper, Tao Liang, Feng Yan, Feng Ren, Jiong Lan, Qiang Lu, Fusheng Zhou, Alex Zhavoronkov, Xiao Ding","doi":"10.1021/acs.jmedchem.4c03205","DOIUrl":"10.1021/acs.jmedchem.4c03205","url":null,"abstract":"Fibroblast growth factor receptors (FGFRs) are established oncogenic drivers in various solid tumors. However, the approved FGFR inhibitors face challenges with acquired resistance and dose-limiting adverse effects associated with FGFR1/4 inhibition, limiting therapeutic efficacy. Herein, we systematically explored linker and electrophile moieties based on the pyrrolopyrazine carboxamide core and identified aniline α-fluoroacrylamide as an effective covalent warhead. Compound 10 potently inhibited FGFR2 and FGFR3, even in the context of common inhibitor-resistance mutations, including in the gatekeeper, molecular brake, and activation loop regions. Compound 10 spared FGFR1/4 and other kinases without causing diarrhea and serum phosphate elevation in vivo. Oral administration of compound 10 induced tumor stasis or regression in the SNU-16 gastric cancer model with favorable pharmacokinetics and robust pharmacodynamic suppression.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":"3886-3899"},"PeriodicalIF":6.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062226","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}

引用次数: 0

Discovery, Optimization, and Preclinical Pharmacology of EP652, a METTL3 Inhibitor with Efficacy in Liquid and Solid Tumor Models.

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-02-13 Epub Date: 2025-01-30 DOI: 10.1021/acs.jmedchem.4c02225

Guillaume Dutheuil, Killian Oukoloff, Julien Korac, François Lenoir, Mohamed El Bousmaqui, Nicolas Probst, Alexey Lapin, Galina Nakhabina, Catherine Sorlet, Nicolas Parmentier, Delphine Karila, Nugzar Ghavtadze, Paméla Casault, Stephen Claridge, Selma Sapmaz, Martin J Slater, Graeme L Fraser

{"title":"Discovery, Optimization, and Preclinical Pharmacology of EP652, a METTL3 Inhibitor with Efficacy in Liquid and Solid Tumor Models.","authors":"Guillaume Dutheuil, Killian Oukoloff, Julien Korac, François Lenoir, Mohamed El Bousmaqui, Nicolas Probst, Alexey Lapin, Galina Nakhabina, Catherine Sorlet, Nicolas Parmentier, Delphine Karila, Nugzar Ghavtadze, Paméla Casault, Stephen Claridge, Selma Sapmaz, Martin J Slater, Graeme L Fraser","doi":"10.1021/acs.jmedchem.4c02225","DOIUrl":"10.1021/acs.jmedchem.4c02225","url":null,"abstract":"METTL3 is the RNA methyltransferase predominantly responsible for the addition of N6-methyladenosine (m6A), the most abundant modification to mRNA. The prevalence of m6A and the activity and expression of METTL3 have been linked to the appearance and progression of acute myeloid leukemia (AML), thereby making METTL3 an attractive target for cancer therapeutics. We report herein the discovery and optimization of small-molecule inhibitors of METTL3, culminating in the selection of EP652 as an in vivo proof-of-concept compound. EP652 potently inhibits the enzymatic activity of METTL3, has favorable PK parameters, and demonstrates efficacy in preclinical oncology models, indicating that pharmacological inhibition of METTL3 is a viable strategy for the treatment of liquid and solid tumors.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":"2981-3003"},"PeriodicalIF":6.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062233","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}

引用次数: 0