Yubai Zhou, Pratima Chapagain, Desmarini Desmarini, Dilipkumar Uredi, Michael A Stashko, Hundaol Huluka, Lucia E Rameh, Julianne T Djordjevic, Raymond D Blind, Xiaodong Wang
{"title":"Design, Synthesis, and Cellular Characterization of a New Class of IPMK Kinase Inhibitors.","authors":"Yubai Zhou, Pratima Chapagain, Desmarini Desmarini, Dilipkumar Uredi, Michael A Stashko, Hundaol Huluka, Lucia E Rameh, Julianne T Djordjevic, Raymond D Blind, Xiaodong Wang","doi":"10.1021/acs.jmedchem.5c00015","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00015","url":null,"abstract":"<p><p>The kinase activity of human inositol phosphate multikinase (IPMK) is required for the synthesis of higher-order inositol phosphate signaling molecules, regulation of gene expression, and control of the cell cycle. Here, we report a novel series of highly potent IPMK inhibitors. The first-generation IPMK inhibitor <b>1</b> (UNC7437) decreased cellular proliferation and tritiated inositol phosphate levels in metabolically labeled human U251-MG glioblastoma cells. It also impacted the transcriptome of these cells, selectively regulating 993 genes enriched in cancer, epithelial-to-mesenchymal transition (EMT), and inflammatory and viral infection pathways, consistent with anticancer growth activity. Extensive optimization of <b>1</b> led to <b>14</b> (UNC9750) with improved pharmacokinetic properties. Compound <b>14</b> inhibited cellular accumulation of InsP<sub>5</sub>, the direct product of IPMK kinase activity, while having no effect on either InsP<sub>6</sub> or InsP<sub>7</sub> levels. These studies suggest that rapid chemical inhibition of IPMK induces a novel InsP<sub>5</sub> metabolic signature, providing new biological insights into inositol phosphate metabolism and signaling.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144705770","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}
Su Hyun Ji,Miso Kang,Hyomin Ahn,Soo Yeon Baek,In-Gyun Lee,Hanul Jeon,Hwan Won Chung,Dong Kyun Han,Seoyeong Yang,Hyebin Lee,Yeseul Kim,Ji Hun Wi,Jeehee Lee,Younghun Yoo,Sungbae Kang,Mihue Jang,Byungsun Jeon,Nam-Jung Kim,Chiman Song,Sanghee Lee,Seo-Jung Han
{"title":"Identification of 5,7-Dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one Derivatives as ENPP1 Inhibitors for STING Pathway-Mediated Immunotherapy.","authors":"Su Hyun Ji,Miso Kang,Hyomin Ahn,Soo Yeon Baek,In-Gyun Lee,Hanul Jeon,Hwan Won Chung,Dong Kyun Han,Seoyeong Yang,Hyebin Lee,Yeseul Kim,Ji Hun Wi,Jeehee Lee,Younghun Yoo,Sungbae Kang,Mihue Jang,Byungsun Jeon,Nam-Jung Kim,Chiman Song,Sanghee Lee,Seo-Jung Han","doi":"10.1021/acs.jmedchem.5c01021","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01021","url":null,"abstract":"A novel small-molecule ENPP1 inhibitor, compound 31 featuring a pyrrolopyrimidinone core, was identified. Compound 31 exhibited potent ENPP1 inhibition with an IC50 of 14.68 nM and effectively activated the STING pathway in cell lines. In addition, 31 promoted cytokine release, thereby enhancing innate immune response. Moreover, 31 demonstrated favorable ADMET properties. Compound 31 displayed significant antitumor efficacy in 4T1 and CT26 syngeneic mouse models without notable toxicity. These findings highlight the potential of 31 as a promising compound for cancer immunotherapy by enhancing STING-mediated immune activation and improving responses to immune checkpoint inhibitors.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"115 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701265","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}
Hans Kelgtermans,Maxim De Wachter,Stijn Heyndrickx,Sandy El Bkassiny,Tatiana Lacarriere,Chris Laruelle,Jörg Heiermann,Wendy van Bruggen,Katarzyna Drabik,Denis Bucher,Thomas Coudrat,Emilie Jigorel,Kenneth Goossens,Michael Drennan,Martine Vrints,Maarten Verbeeck,Bas Housmans,Damien Ronsse,David Moreno-Delgado,Vahid Nassiri,Mia Jans,Maarten Gees,Emanuelle Wakselman,Line Oste,Monica Borgonovi,Elena Borregán-Ochando,Vladyslav Sushko,Alain Monjardet,Camille Dusserre,Frederique Van Acker,Anouk Blaauw,Stephanie Lavazais,Catherine Jagerschmidt,Didier Merciris,Michael Török-Schafroth,Christian A Seemayer,Katja Conrath,Fabrice A Kolb,Pierre Raboisson,Reginald Brys,David Amantini,Romain Gosmini,Alexis Denis,Juan-Miguel Jimenez,Steve De Vos,Nicolas Desroy
{"title":"Structure-Activity Relationship Guided Scaffold Hopping Resulted in the Identification of GLPG4970, a Highly Potent Dual SIK2/SIK3 Inhibitor.","authors":"Hans Kelgtermans,Maxim De Wachter,Stijn Heyndrickx,Sandy El Bkassiny,Tatiana Lacarriere,Chris Laruelle,Jörg Heiermann,Wendy van Bruggen,Katarzyna Drabik,Denis Bucher,Thomas Coudrat,Emilie Jigorel,Kenneth Goossens,Michael Drennan,Martine Vrints,Maarten Verbeeck,Bas Housmans,Damien Ronsse,David Moreno-Delgado,Vahid Nassiri,Mia Jans,Maarten Gees,Emanuelle Wakselman,Line Oste,Monica Borgonovi,Elena Borregán-Ochando,Vladyslav Sushko,Alain Monjardet,Camille Dusserre,Frederique Van Acker,Anouk Blaauw,Stephanie Lavazais,Catherine Jagerschmidt,Didier Merciris,Michael Török-Schafroth,Christian A Seemayer,Katja Conrath,Fabrice A Kolb,Pierre Raboisson,Reginald Brys,David Amantini,Romain Gosmini,Alexis Denis,Juan-Miguel Jimenez,Steve De Vos,Nicolas Desroy","doi":"10.1021/acs.jmedchem.5c01401","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01401","url":null,"abstract":"Inhibition of salt-inducible kinases (SIKs) SIK1, SIK2, and SIK3 represents a new potential therapeutic approach for autoimmune and inflammatory disease treatment via modulation of pro-inflammatory and immunoregulatory pathways, particularly inhibition of SIK2 and SIK3. After discovering a new chemotype for SIK inhibition, further optimization of potency, selectivity, ADMET and PK properties resulted in a 1,6-naphtyridine containing molecule GLPG4876 (7). However, 7 was clastogenic when examined in vivo in rat micronucleus assays, preventing further development. Overlay of 7 with GLPG3970 (6) within the SIK3 protein structure inspired the design of pyridine derivatives, leading to the identification of GLPG4970 (8). Compound 8 was negative in genotoxicity screening assays and demonstrated potent SIK2/SIK3 inhibition, for which isoform selectivity was determined in a cellular context. Compound 8 displayed improved potency compared with previously reported SIK inhibitors in biochemical and phenotypic cellular assays, and showed dose-dependent activity in disease relevant mouse pharmacological models of colitis.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"704 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701266","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}
Joachim Bröker,Alex G Waterson,Timothy R Hodges,Jason R Abbott,Allison Arnold,Jark Böttcher,Nina Braun,Jianwen Cui,Julian E Fuchs,Thomas Gerstberger,Sebastian Gogg,Sabine Hanner,Lorenz Herdeis,Lucas W Howell,Andreas Mantoulidis,Moriz Mayer,Jason Phan,Francesca Rocchetti,Kyra Sankar,Dhruba Sarkar,Otmar Schaaf,John L Sensintaffar,Qi Sun,Tobias Wunberg,Stephen W Fesik
{"title":"Discovery of BI-2493, a Pan-KRAS Inhibitor Showing In Vivo Efficacy.","authors":"Joachim Bröker,Alex G Waterson,Timothy R Hodges,Jason R Abbott,Allison Arnold,Jark Böttcher,Nina Braun,Jianwen Cui,Julian E Fuchs,Thomas Gerstberger,Sebastian Gogg,Sabine Hanner,Lorenz Herdeis,Lucas W Howell,Andreas Mantoulidis,Moriz Mayer,Jason Phan,Francesca Rocchetti,Kyra Sankar,Dhruba Sarkar,Otmar Schaaf,John L Sensintaffar,Qi Sun,Tobias Wunberg,Stephen W Fesik","doi":"10.1021/acs.jmedchem.5c00576","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00576","url":null,"abstract":"KRAS is one of the most highly validated cancer targets. Here we describe the design and synthesis of two reversible pan-KRAS inhibitors, BI-2865 and BI-2493. From our KRASG12C inhibitor program, we identified BI-2865, a potent noncovalent KRAS inhibitor that showed cellular activity against a broad spectrum of KRAS alleles and selectivity against HRAS and NRAS. Spirocyclization led to the discovery of BI-2493, a highly rigid analogue exhibiting better potency, metabolic stability, and permeability. BI-2493 shows in vivo efficacy in various KRAS mutant and KRAS wild-type amplified xenograft models and represents a promising starting point for further optimization.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"47 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701144","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":"Iron Uptake Systems: Chemical Tools for Advancing Infectious Disease Treatment and Diagnosis.","authors":"Dianmo Ni, Gang Liu","doi":"10.1021/acs.jmedchem.5c01023","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01023","url":null,"abstract":"<p><p>Microorganisms require iron acquisition, particularly in the form of Fe<sup>3+</sup> ions from the external environment, for survival. Siderophores are low-molecular-weight compounds secreted by microorganisms that chelate Fe<sup>3+</sup> ions and facilitate their transport into cells. This process forms an Fe<sup>3+</sup> uptake system in conjunction with specific transporters, enabling microorganisms to meet their iron requirements. A promising strategy involves utilizing the Fe<sup>3+</sup> transport mechanism to deliver siderophore-cargo conjugates into microbial cells, thereby enabling the treatment and diagnosis of infectious diseases, including those caused by drug-resistant bacteria. In this perspective, we systematically evaluate each type of siderophore-antibiotic/fluorophore conjugate and its associated therapeutic and diagnostic outcomes. Through this perspective, we aim to further develop the iron uptake strategy as a means to address the increasingly severe global public health challenge of antimicrobial resistance and to achieve rapid and ultrasensitive diagnosis of infections, encompassing but not limited to bacterial and fungal infections.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144715008","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}
Qinying Yu, Li Ma, Leah M Norona, Peter S Dragovich, Jianshuang Wang, Shuai Wang, Yi-Chen Chen, S Cyrus Khojasteh, Jane R Kenny, Brian J Dean, Cornelis E C A Hop, Sarah J Robinson, Ke Sherry Li, Lionel Cheruzel, Aaron Fullerton, Yunxing Cheng, Mingtao He, Xinpeng Wang, Klarissa D Jackson, Zhengyin Yan, Donglu Zhang
{"title":"Elucidating Molecular Mechanisms of Drug-Induced Hepatotoxicity of Lapatinib.","authors":"Qinying Yu, Li Ma, Leah M Norona, Peter S Dragovich, Jianshuang Wang, Shuai Wang, Yi-Chen Chen, S Cyrus Khojasteh, Jane R Kenny, Brian J Dean, Cornelis E C A Hop, Sarah J Robinson, Ke Sherry Li, Lionel Cheruzel, Aaron Fullerton, Yunxing Cheng, Mingtao He, Xinpeng Wang, Klarissa D Jackson, Zhengyin Yan, Donglu Zhang","doi":"10.1021/acs.jmedchem.5c01305","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01305","url":null,"abstract":"<p><p>DILI (drug-induced liver injury) remains a critical liability in drug discovery and development. However, there are few in vitro and preclinical models to predict DILI, and the knowledge of DILI molecular targets is even more limited. The lapatinib (<b>1</b>) prescription label carries a black box warning for idiosyncratic hepatotoxicity and this has prompted numerous studies aimed at understanding the underlying molecular mechanisms. Using lapatinib as a tool molecule, we first identified a novel P450 3A5-catalyzed bioactivation, leading to highly reactive quinone methide (QM) metabolites formed after ortho- and para-hydroxylation at the 3F-benzyl ring, followed by self-immolation. The structure and activity relationship (SAR) studies of lapatinib analogs characterized the positional substitute-dependent quinone methide formation. Proteomics data revealed that quinone methide formation through bioactivation followed by simultaneous covalent modifications/functional disruption of several cellular enzymes in mitochondrial energy-production and reduction of oxidative stress could lead to mitochondrial stress and overall hepatotoxicity.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144715007","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}
Zulma Santisteban Valencia, Jennifer Kingston, Filip Miljković, Hannah Rowbottom, Nadia Mann, Sophie Davies, Martin Ekblad, Silvio Di Castro, Karolina Kwapień, Erik Malmerberg, Stig D. Friis, Thomas Lundbäck*, Tomas Leek* and Johan Wernevik*,
{"title":"","authors":"Zulma Santisteban Valencia, Jennifer Kingston, Filip Miljković, Hannah Rowbottom, Nadia Mann, Sophie Davies, Martin Ekblad, Silvio Di Castro, Karolina Kwapień, Erik Malmerberg, Stig D. Friis, Thomas Lundbäck*, Tomas Leek* and Johan Wernevik*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 14","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":6.8,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.5c01870","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144685402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rajamanikkam Kamaraj, Ivana Mejdrová, Maria Krutakova, Tomas Smutny, Kryštof Škach, Klara Dohnalova, Lucie Smutna, Dharani Sai Sreekanth Nellore, Jan Dusek, Karel Chalupsky, Jana Hricová, Thales Kronenberger, Aaron Stahl, Markus Templin, Albert Braeuning, Radim Nencka* and Petr Pavek*,
{"title":"","authors":"Rajamanikkam Kamaraj, Ivana Mejdrová, Maria Krutakova, Tomas Smutny, Kryštof Škach, Klara Dohnalova, Lucie Smutna, Dharani Sai Sreekanth Nellore, Jan Dusek, Karel Chalupsky, Jana Hricová, Thales Kronenberger, Aaron Stahl, Markus Templin, Albert Braeuning, Radim Nencka* and Petr Pavek*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 14","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":6.8,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.4c03134","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144685410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Overcoming E3 Ligase-Mediated Resistance: Development of Novel Hydrophobic Tagging-Based Degraders Targeting ALK Protein.","authors":"Shaowen Xie,Jingjie Zhu,Fangyi Zhan,Dazhi Feng,Chen He,Lihua Liu,Jia Xie,Jingyu Liu,Ming Zhong,Xingting Zhang,Jinyi Xu,Hong Yao,Shengtao Xu","doi":"10.1021/acs.jmedchem.5c00488","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00488","url":null,"abstract":"Traditional PROTACs, despite their groundbreaking role in targeted protein degradation (TPD), rely on E3 ubiquitin ligases and are vulnerable to resistance. In this study, we discovered norbornene- and bornane-based hydrophobic tags (HyTs) that efficiently degrade anaplastic lymphoma kinase (ALK). Notably, a novel hydrophobic tag, bornane was first identified. Both norbornene-based HyT J26 and bornane-based HyT J21 demonstrated significant degradation and antiproliferative activity in vitro. J26 achieves effective degradation of the EML4-ALK fusion protein in H3122 cells with CRBN expression knocked down via siRNA. In vivo, J26 significantly suppresses tumor growth with moderate oral bioavailability. Remarkably, J26 effectively targets ALK through the Hsp70 chaperone system and the ubiquitin-proteasome pathway, by passing the need for E3 ligase CRBN. This feature addresses a potential resistance mechanism arising from E3 ligase downregulation, thereby enhancing the potential of HyT technology in precision oncology.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"17 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693346","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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