Pub Date : 2026-01-26DOI: 10.1021/acs.jmedchem.5c03109
Jeeyeon Kim, Kyeongwon Moon, Jihun Kim, Sung-Jun Park, Nari Kim, Yonggyu Jung, Yoonsuk Lee, Kyoungmin Lee, Wokchul Yoo, Jong Hoon Kim, Byeong-Won Kim, Daseul Kim, Hyun-Ju Park, Jaeheon Lee, Pargat Singh, In Su Kim
Capping is a natural and distinctive modification that occurs at the 5′-end of eukaryotic messenger RNA (mRNA), which regulates biological functions for gene expression events. Recently, the synthetic variation of a 5′-cap element has attracted considerable attention for improving the transcriptional efficiency and stability of mRNA. Herein, we describe the synthesis and biological evaluation of trinucleotide 5′-capping agents with 2′- and 3′-ribose modifications. The 3′-O-mesylated m7GpppAmG 43 demonstrated a high capping efficiency of 97.1%, comparable to the commercial CleanCapAG(3′OMe) 9. Furthermore, compound 43 exhibited a potent translational ability in the dual luciferase reporter assay, which was 1.8-fold higher than that of compound 9. Moreover, compound 43 was resistant against decapping enzymes (DcpS and hDcp2), thereby revealing its stability under biological conditions. In vivo translational studies demonstrated that lipid nanoparticle 43a, formulated from compound 43 with firefly luciferase mRNA, exhibited intense bioluminescence, supporting its translational competence.
{"title":"Synthesis and Translational Assessment of Trinucleotide 5′-Cap Analogs for Messenger Ribonucleic Acid-Based Therapeutics","authors":"Jeeyeon Kim, Kyeongwon Moon, Jihun Kim, Sung-Jun Park, Nari Kim, Yonggyu Jung, Yoonsuk Lee, Kyoungmin Lee, Wokchul Yoo, Jong Hoon Kim, Byeong-Won Kim, Daseul Kim, Hyun-Ju Park, Jaeheon Lee, Pargat Singh, In Su Kim","doi":"10.1021/acs.jmedchem.5c03109","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03109","url":null,"abstract":"Capping is a natural and distinctive modification that occurs at the 5′-end of eukaryotic messenger RNA (mRNA), which regulates biological functions for gene expression events. Recently, the synthetic variation of a 5′-cap element has attracted considerable attention for improving the transcriptional efficiency and stability of mRNA. Herein, we describe the synthesis and biological evaluation of trinucleotide 5′-capping agents with 2′- and 3′-ribose modifications. The 3′-<i>O</i>-mesylated m<sup>7</sup>GpppA<sub>m</sub>G <b>43</b> demonstrated a high capping efficiency of 97.1%, comparable to the commercial CleanCapAG(3′OMe) <b>9</b>. Furthermore, compound <b>43</b> exhibited a potent translational ability in the dual luciferase reporter assay, which was 1.8-fold higher than that of compound <b>9</b>. Moreover, compound <b>43</b> was resistant against decapping enzymes (DcpS and hDcp2), thereby revealing its stability under biological conditions. <i>In vivo</i> translational studies demonstrated that lipid nanoparticle <b>43a</b>, formulated from compound <b>43</b> with firefly luciferase mRNA, exhibited intense bioluminescence, supporting its translational competence.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"100 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044853","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}
Pub Date : 2026-01-26DOI: 10.1021/acs.jmedchem.5c03037
Eslam Roshdy,Eva Řezníčková,Mostafa M. Elbadawi,Ismail Celik,Simone Giovannuzzi,Denisa Veselá,Veronika Vojáčková,Petra Krňávková,Alessio Nocentini,Claudiu T. Supuran,Vladimír Kryštof,Wagdy M. Eldehna,Manabu Abe
Leukemia remains a challenging hematological malignancy, with limited therapeutic options. To address this unmet need, we report quinoline–sulfonamide hybrids as first-in-class dual inhibitors of platelet-derived growth factor receptor (PDGFR) and carbonic anhydrase (CA) IX/XII. Structure–activity relationship studies identified compound 9d as a potent lead, exhibiting strong inhibition of PDGFRA (IC50 = 20 nM) and CA IX/XII (KI = 93.3 and 80.0 nM, respectively), along with exceptional antiproliferative activity in FIP1L1–PDGFRA-driven EOL-1 cells (GI50 = 2 nM), comparable to clinical agents. Mechanistic analyses revealed that 9d effectively abrogates PDGFRA signaling, induces G0/G1 cell-cycle arrest, and triggers apoptosis. Molecular docking and 200 ns molecular dynamics simulations supported stable dual binding of 9d within the ATP-binding pocket of PDGFR and the catalytic cleft of CA IX. By simultaneously targeting oncogenic PDGFRA signaling and hypoxia-driven pH regulation (CA IX/XII), 9d represents a promising lead for preclinical development in PDGFR/CA IX/XII-driven leukemias.
{"title":"First-in-Class Dual PDGFR/Carbonic Anhydrase IX/XII Inhibitors: 6,7-Dimethoxyquinoline-Sulfonamides as Promising Antileukemic Agents","authors":"Eslam Roshdy,Eva Řezníčková,Mostafa M. Elbadawi,Ismail Celik,Simone Giovannuzzi,Denisa Veselá,Veronika Vojáčková,Petra Krňávková,Alessio Nocentini,Claudiu T. Supuran,Vladimír Kryštof,Wagdy M. Eldehna,Manabu Abe","doi":"10.1021/acs.jmedchem.5c03037","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03037","url":null,"abstract":"Leukemia remains a challenging hematological malignancy, with limited therapeutic options. To address this unmet need, we report quinoline–sulfonamide hybrids as first-in-class dual inhibitors of platelet-derived growth factor receptor (PDGFR) and carbonic anhydrase (CA) IX/XII. Structure–activity relationship studies identified compound 9d as a potent lead, exhibiting strong inhibition of PDGFRA (IC50 = 20 nM) and CA IX/XII (KI = 93.3 and 80.0 nM, respectively), along with exceptional antiproliferative activity in FIP1L1–PDGFRA-driven EOL-1 cells (GI50 = 2 nM), comparable to clinical agents. Mechanistic analyses revealed that 9d effectively abrogates PDGFRA signaling, induces G0/G1 cell-cycle arrest, and triggers apoptosis. Molecular docking and 200 ns molecular dynamics simulations supported stable dual binding of 9d within the ATP-binding pocket of PDGFR and the catalytic cleft of CA IX. By simultaneously targeting oncogenic PDGFRA signaling and hypoxia-driven pH regulation (CA IX/XII), 9d represents a promising lead for preclinical development in PDGFR/CA IX/XII-driven leukemias.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"51 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044976","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}
Pub Date : 2026-01-26DOI: 10.1021/acs.jmedchem.5c02609
Jacob L. Capener, Thomas W. Kramer, Frances M. Bashore, Emily Flory, Fengling Li, Blair L. Strang, Alison D. Axtman
The casein kinase 1γ (CK1γ) subfamily, while severely understudied, is implicated in diverse disease–relevant pathways, including WNT signaling and human cytomegalovirus (HCMV) replication. While genetic tools exist to study CK1γ, the selective inhibition of CK1γ through pharmacological means remains underexplored. Chemical probes, or potent and selective inhibitors, remain one of the most powerful pharmacological tools for uncovering protein biology. Herein, we developed several novel assays for assessing target engagement with the CK1γ subfamily in cells. Enabled by these assays, we conducted a comprehensive structure–activity relationship (SAR) campaign to develop the first chemical probe, SGC-CK1γ-1, for the CK1γ subfamily. SGC-CK1γ-1, which was developed alongside a structurally related negative control compound, potently and selectively inhibited the CK1γ kinases in living cells, plus inhibited both WNT signaling and human cytomegalovirus replication.
{"title":"Development of a Chemical Probe to Enable Characterization of the Casein Kinase 1γ Subfamily","authors":"Jacob L. Capener, Thomas W. Kramer, Frances M. Bashore, Emily Flory, Fengling Li, Blair L. Strang, Alison D. Axtman","doi":"10.1021/acs.jmedchem.5c02609","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02609","url":null,"abstract":"The casein kinase 1γ (CK1γ) subfamily, while severely understudied, is implicated in diverse disease–relevant pathways, including WNT signaling and human cytomegalovirus (HCMV) replication. While genetic tools exist to study CK1γ, the selective inhibition of CK1γ through pharmacological means remains underexplored. Chemical probes, or potent and selective inhibitors, remain one of the most powerful pharmacological tools for uncovering protein biology. Herein, we developed several novel assays for assessing target engagement with the CK1γ subfamily in cells. Enabled by these assays, we conducted a comprehensive structure–activity relationship (SAR) campaign to develop the first chemical probe, SGC-CK1γ-1, for the CK1γ subfamily. SGC-CK1γ-1, which was developed alongside a structurally related negative control compound, potently and selectively inhibited the CK1γ kinases in living cells, plus inhibited both WNT signaling and human cytomegalovirus replication.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"87 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044850","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}
Pub Date : 2026-01-26DOI: 10.1021/acs.jmedchem.5c00997
Lorenzo Cianni,Kathryn Jacobs,Sergei Grintsevich,Sophie Lyssens,Eline Roeyen,Koen Augustyns,Maya Berg,Hans De Winter,Guido R. Y. de Meyer,Wim Martinet,Patrizia Agostinis,Gabriele Bergers,Pieter Van der Veken
Autophagy, the primary lysosomal degradation pathway, plays a key role in cell survival and homeostasis. In tumors, it is upregulated to support cancer cell plasticity, adaptation to the microenvironment, and therapy resistance, making its inhibition an attractive therapeutic strategy. However, since autophagy is essential in healthy tissues, selective inhibition in tumors is critical. To address this, we designed inhibitors of two autophagy initiation factors (ULK1/2 and VPS34) equipped with tumor-targeting vectors. Our most promising candidates combine a low-nanomolar ULK1/2 inhibitory scaffold with an RGR-sequence targeting peptide. These compounds were validated across in vitro, in cellulo, and in vivo models, demonstrating selective activity and preserved efficacy. As the first examples of tumor-targeted autophagy inhibitors, they open new avenues for developing tissue-specific modulators of autophagy, with potential applications in oncology and beyond.
{"title":"Vectorized ULK1/2 and VPS34 Inhibitors for Tissue-Selective Autophagy Inhibition in Oncology","authors":"Lorenzo Cianni,Kathryn Jacobs,Sergei Grintsevich,Sophie Lyssens,Eline Roeyen,Koen Augustyns,Maya Berg,Hans De Winter,Guido R. Y. de Meyer,Wim Martinet,Patrizia Agostinis,Gabriele Bergers,Pieter Van der Veken","doi":"10.1021/acs.jmedchem.5c00997","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00997","url":null,"abstract":"Autophagy, the primary lysosomal degradation pathway, plays a key role in cell survival and homeostasis. In tumors, it is upregulated to support cancer cell plasticity, adaptation to the microenvironment, and therapy resistance, making its inhibition an attractive therapeutic strategy. However, since autophagy is essential in healthy tissues, selective inhibition in tumors is critical. To address this, we designed inhibitors of two autophagy initiation factors (ULK1/2 and VPS34) equipped with tumor-targeting vectors. Our most promising candidates combine a low-nanomolar ULK1/2 inhibitory scaffold with an RGR-sequence targeting peptide. These compounds were validated across in vitro, in cellulo, and in vivo models, demonstrating selective activity and preserved efficacy. As the first examples of tumor-targeted autophagy inhibitors, they open new avenues for developing tissue-specific modulators of autophagy, with potential applications in oncology and beyond.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"44 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146045008","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}
Pub Date : 2026-01-26DOI: 10.1021/acs.jmedchem.5c03217
Jan Vietor, Romy Busch, Úrsula López-García, Tanja Stiller, Anna Maria Thommes, Christian Gege, Daniel Merk
The nerve growth factor IB-like receptors (NR4A) are (neuro)protective transcription factors as part of the immediate early response and hold potential in various pathologies, including neurodegeneration. Despite recent progress in NR4A ligand development, high-quality chemical tools to probe phenotypic effects of NR4A modulation are still rare, and a selective agonist with strong efficacy is lacking. Here, we developed a potent and selective NR4A activator equipped with distinctly high agonist efficacy building on the scaffold of the dihydroorotate dehydrogenase inhibitor and nuclear receptor-related 1 agonist vidofludimus. We identified structural modifications conveying potency, selectivity, and efficacy via systematic structure–activity relationship elucidation, and fusion of favored motifs eventually enabled multiparameter optimization to a chemical tool meeting highest quality criteria for biological studies.
{"title":"Structural Tuning of Vidofludimus for High-Efficacy NR4A Agonism","authors":"Jan Vietor, Romy Busch, Úrsula López-García, Tanja Stiller, Anna Maria Thommes, Christian Gege, Daniel Merk","doi":"10.1021/acs.jmedchem.5c03217","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03217","url":null,"abstract":"The nerve growth factor IB-like receptors (NR4A) are (neuro)protective transcription factors as part of the immediate early response and hold potential in various pathologies, including neurodegeneration. Despite recent progress in NR4A ligand development, high-quality chemical tools to probe phenotypic effects of NR4A modulation are still rare, and a selective agonist with strong efficacy is lacking. Here, we developed a potent and selective NR4A activator equipped with distinctly high agonist efficacy building on the scaffold of the dihydroorotate dehydrogenase inhibitor and nuclear receptor-related 1 agonist vidofludimus. We identified structural modifications conveying potency, selectivity, and efficacy via systematic structure–activity relationship elucidation, and fusion of favored motifs eventually enabled multiparameter optimization to a chemical tool meeting highest quality criteria for biological studies.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"44 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044851","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}
Pub Date : 2026-01-25DOI: 10.1021/acs.jmedchem.5c02600
Rui Wang,Xiao-Dong Wang,Ming-Hao Hu
Liver cancer, a leading cause of cancer-related mortality, is characterized by intrinsic and acquired therapeutic resistance linked to dysregulated programmed cell death pathways. Apoptosis evasion, driven by p53 mutations or antiapoptotic protein overexpression, and autophagy upregulation, which sustains cancer cell survival under stress, are critical barriers to effective treatment. This study introduced XAN-5, a novel mitochondrial DNA G-quadruplex (mtG4)-targeting tetrahydroxanthylium ligand that can simultaneously induce apoptosis and inhibit autophagy. Mechanistically, XAN-5 bound mtG4s, triggering mitochondrial dysfunction, reactive oxygen species overproduction, and caspase-dependent apoptosis. Concurrently, XAN-5 disrupted autophagic flux, evidenced by reduced LC3B-II conversion and p62 accumulation. In a mouse liver cancer model, XAN-5 inhibited tumor growth while enhancing tumor-infiltrating CD4+ and CD8+ T cells. These findings highlighted the unique capacity of XAN-5 to target two resistance mechanisms, offering a paradigm shift in liver cancer therapy.
肝癌是癌症相关死亡的主要原因，其特点是与失调的程序性细胞死亡途径相关的内在和获得性治疗耐药性。由p53突变或抗凋亡蛋白过度表达驱动的细胞凋亡逃避，以及维持癌细胞在应激下存活的自噬上调，是有效治疗的关键障碍。本研究引入了一种新的线粒体DNA g -四重体（mtG4）靶向四羟基anthanthum配体XAN-5，它可以同时诱导细胞凋亡和抑制自噬。从机制上说，XAN-5结合mtG4s，引发线粒体功能障碍、活性氧过量产生和caspase依赖性细胞凋亡。同时，XAN-5破坏了自噬通量，证明了LC3B-II转化和p62积累的减少。在小鼠肝癌模型中，XAN-5抑制肿瘤生长，同时增强肿瘤浸润的CD4+和CD8+ T细胞。这些发现强调了XAN-5靶向两种耐药机制的独特能力，为肝癌治疗提供了范式转变。
{"title":"Novel Tetrahydroxanthylium-Based Ligands Targeting Mitochondrial DNA G-Quadruplex Structures for Concurrent Induction of Apoptosis and Inhibition of Autophagy in Liver Cancer.","authors":"Rui Wang,Xiao-Dong Wang,Ming-Hao Hu","doi":"10.1021/acs.jmedchem.5c02600","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02600","url":null,"abstract":"Liver cancer, a leading cause of cancer-related mortality, is characterized by intrinsic and acquired therapeutic resistance linked to dysregulated programmed cell death pathways. Apoptosis evasion, driven by p53 mutations or antiapoptotic protein overexpression, and autophagy upregulation, which sustains cancer cell survival under stress, are critical barriers to effective treatment. This study introduced XAN-5, a novel mitochondrial DNA G-quadruplex (mtG4)-targeting tetrahydroxanthylium ligand that can simultaneously induce apoptosis and inhibit autophagy. Mechanistically, XAN-5 bound mtG4s, triggering mitochondrial dysfunction, reactive oxygen species overproduction, and caspase-dependent apoptosis. Concurrently, XAN-5 disrupted autophagic flux, evidenced by reduced LC3B-II conversion and p62 accumulation. In a mouse liver cancer model, XAN-5 inhibited tumor growth while enhancing tumor-infiltrating CD4+ and CD8+ T cells. These findings highlighted the unique capacity of XAN-5 to target two resistance mechanisms, offering a paradigm shift in liver cancer therapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"44 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044650","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}
Pub Date : 2026-01-24DOI: 10.1021/acs.jmedchem.5c03412
Jie Yuan,Yuanyuan Wang,Minhui Liu,Dan Cheng,Lin Yuan
Photodynamic therapy (PDT) and photothermal therapy (PTT), as two advanced noninvasive optical therapeutic strategies, have attracted considerable attention for their high spatiotemporal selectivity and minimal side effects. However, most existing synergistic therapeutic systems rely on multicomponent nanocomposites, whose complex design and preparation as well as cumbersome operation severely limit their application. Therefore, developing single-component therapeutic agents capable of synergistically achieving both PDT and PTT under a single excitation wavelength has emerged as a frontier and core challenge in this field. Herein, a 1,4-diethyldecahydroquinoline ring was introduced into the cyanine backbone structure to construct a novel phototherapeutic agent, IR805, with good stability and both PDT and PTT functions. Importantly, the nanomodified NanoIR805-PEG nanoparticles could effectively kill tumor cells or eliminate tumors in both in vitro and in vivo antitumor processes. This study will provide new ideas and insights into constructing new types of phototherapeutic agents with both PDT and PTT functions.
{"title":"Engineering a NIR-II Fluorescence/Photoacoustic Imaging Nano Phototherapy Reagent for Combined Photodynamic and Photothermal Therapies for Tumor.","authors":"Jie Yuan,Yuanyuan Wang,Minhui Liu,Dan Cheng,Lin Yuan","doi":"10.1021/acs.jmedchem.5c03412","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03412","url":null,"abstract":"Photodynamic therapy (PDT) and photothermal therapy (PTT), as two advanced noninvasive optical therapeutic strategies, have attracted considerable attention for their high spatiotemporal selectivity and minimal side effects. However, most existing synergistic therapeutic systems rely on multicomponent nanocomposites, whose complex design and preparation as well as cumbersome operation severely limit their application. Therefore, developing single-component therapeutic agents capable of synergistically achieving both PDT and PTT under a single excitation wavelength has emerged as a frontier and core challenge in this field. Herein, a 1,4-diethyldecahydroquinoline ring was introduced into the cyanine backbone structure to construct a novel phototherapeutic agent, IR805, with good stability and both PDT and PTT functions. Importantly, the nanomodified NanoIR805-PEG nanoparticles could effectively kill tumor cells or eliminate tumors in both in vitro and in vivo antitumor processes. This study will provide new ideas and insights into constructing new types of phototherapeutic agents with both PDT and PTT functions.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"16 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034024","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}
Pub Date : 2026-01-23DOI: 10.1021/acs.jmedchem.5c02536
Anja Federa,Rastislav Pitek,Orsolya Dömötör,Éva A Enyedy,Alessio Terenzi,Monika Caban,Alessia Stefanelli,Luisa D'Anna,Faye White,Petra Heffeter,Christian R Kowol
Albumin is a promising vehicle for anticancer drug delivery due to its high plasma concentration, long half-life and known tumor accumulation. Drugs can be covalently conjugated to albumin via the free thiol at Cys34, using maleimide chemistry. Interestingly, such strategies have not yet been applied to tyrosine kinase inhibitors (TKIs), e.g. crucial in lung cancer treatment. This study investigates a prodrug delivery system for a derivative of the approved epidermal growth factor receptor (EGFR) inhibitor osimertinib, incorporating a maleimide for albumin binding and a cathepsin B-cleavable valine-citrulline (ValCit) dipeptide for selective drug release. In silico and in vitro studies confirmed the prodrug nature. Additionally, selective albumin-binding and efficient cathepsin B-mediated drug release were demonstrated. In non-small cell lung cancer (NSCLC) xenografts, the prodrug exhibited enhanced anticancer activity compared to osimertinib and a noncleavable glycine-glycine (GlyGly) control. These results highlight covalent albumin-binding as a promising strategy for TKI delivery.
{"title":"Tumor-Targeted Delivery of an EGFR Inhibitor Prodrug via Site-Specific Albumin Conjugation.","authors":"Anja Federa,Rastislav Pitek,Orsolya Dömötör,Éva A Enyedy,Alessio Terenzi,Monika Caban,Alessia Stefanelli,Luisa D'Anna,Faye White,Petra Heffeter,Christian R Kowol","doi":"10.1021/acs.jmedchem.5c02536","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02536","url":null,"abstract":"Albumin is a promising vehicle for anticancer drug delivery due to its high plasma concentration, long half-life and known tumor accumulation. Drugs can be covalently conjugated to albumin via the free thiol at Cys34, using maleimide chemistry. Interestingly, such strategies have not yet been applied to tyrosine kinase inhibitors (TKIs), e.g. crucial in lung cancer treatment. This study investigates a prodrug delivery system for a derivative of the approved epidermal growth factor receptor (EGFR) inhibitor osimertinib, incorporating a maleimide for albumin binding and a cathepsin B-cleavable valine-citrulline (ValCit) dipeptide for selective drug release. In silico and in vitro studies confirmed the prodrug nature. Additionally, selective albumin-binding and efficient cathepsin B-mediated drug release were demonstrated. In non-small cell lung cancer (NSCLC) xenografts, the prodrug exhibited enhanced anticancer activity compared to osimertinib and a noncleavable glycine-glycine (GlyGly) control. These results highlight covalent albumin-binding as a promising strategy for TKI delivery.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"49 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146021332","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}
DNA polymerase theta (Polθ), which mediates microhomology-mediated end joining (MMEJ) in homologous recombination-deficient (HRD) cancers, has recently emerged as a compelling synthetic lethal target. Combining Polθ inhibition with PARP inhibitors represents a promising strategy to overcome PARP inhibitor resistance. Here, we present the discovery of SY-589, a highly potent (ATPase IC50 = 2.29 nM), selective (selectivity index >1800), and orally bioavailable (F = 107%) Polθ helicase inhibitor, which exhibits robust antitumor efficacy in HRD tumors in vitro (CTG IC50 = 2.71 nM). Notably, SY-589 synergized strongly with the PARP inhibitor Olaparib in vitro (Loewe score >20) and in vivo (TGI = 109%), enhancing antitumor effects while permitting reduced Olaparib dosing. Overall, SY-589 is a promising candidate of Polθ inhibitor and has been positioned as a rational combination partner with PARP inhibitors, aiming to overcome PARP inhibitor resistance and mitigate their dose-limiting toxicities.
{"title":"Discovery of SY-589, a Highly Potent and Orally Bioavailable Polθ Helicase Inhibitor for the Treatment of HR-Deficient Tumors.","authors":"Chongxun Ge,Dazhi Feng,Song Shi,Xuzhen Tang,Yaqi Cui,Song Liu,Yunyue Wang,Shuangtian Tang,Xinnan Li,Xianqiang Sun,Daopeng Yuan,Jinyi Xu,Hu He,Hong Yao","doi":"10.1021/acs.jmedchem.5c02689","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02689","url":null,"abstract":"DNA polymerase theta (Polθ), which mediates microhomology-mediated end joining (MMEJ) in homologous recombination-deficient (HRD) cancers, has recently emerged as a compelling synthetic lethal target. Combining Polθ inhibition with PARP inhibitors represents a promising strategy to overcome PARP inhibitor resistance. Here, we present the discovery of SY-589, a highly potent (ATPase IC50 = 2.29 nM), selective (selectivity index >1800), and orally bioavailable (F = 107%) Polθ helicase inhibitor, which exhibits robust antitumor efficacy in HRD tumors in vitro (CTG IC50 = 2.71 nM). Notably, SY-589 synergized strongly with the PARP inhibitor Olaparib in vitro (Loewe score >20) and in vivo (TGI = 109%), enhancing antitumor effects while permitting reduced Olaparib dosing. Overall, SY-589 is a promising candidate of Polθ inhibitor and has been positioned as a rational combination partner with PARP inhibitors, aiming to overcome PARP inhibitor resistance and mitigate their dose-limiting toxicities.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"8 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146021334","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}
Targeted protein degradation is one of the fastest developing fields in medicinal chemistry and chemical biology. Despite significant development in assay technologies and inhibitor discovery, the development of PROTACs remains a challenging endeavor since rational design approaches remain widely elusive. Our workflow eliminates the rate-limiting step of classic synthesis, namely compound purification, and pairs it with high-throughput, semi-automated plate-based synthesis, and direct cellular assay evaluation. We applied this direct-to-biology approach to four diverse targets, demonstrating the general applicability of this technology. PROTAC synthesis was realized by using the highly efficient copper-catalyzed azide-alkyne cycloaddition reaction. This simplified reaction setup enabled synthesis in the nanomole scale with reaction volumes as low as 5 μL. The high-throughput strategy allows hundreds of PROTACs to be synthesized and evaluated within a few days, facilitating comprehensive assessment of target degradability, rapid hit identification, and selection of the most suitable E3 ligase for degrader development.
{"title":"Click. Screen. Degrade. A Miniaturized D2B Workflow for Rapid PROTAC Discovery.","authors":"Marko Mitrović,Francesco Aleksy Greco,Yiliam Cruz García,Aleksandar Lučić,Lasse Hoffmann,Rohit Chander,Julia Schönfeld,Nick Liebisch,Saran Aswathaman Sivashanmugam,Martin Peter Schwalm,Markus Egner,Max Lewandowski,Daniel Merk,Viktoria Morasch,Elmar Wolf,Susanne Müller,Thomas Hanke,Ewgenij Proschak,Kerstin Hiesinger,Stefan Knapp","doi":"10.1021/acs.jmedchem.5c02543","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02543","url":null,"abstract":"Targeted protein degradation is one of the fastest developing fields in medicinal chemistry and chemical biology. Despite significant development in assay technologies and inhibitor discovery, the development of PROTACs remains a challenging endeavor since rational design approaches remain widely elusive. Our workflow eliminates the rate-limiting step of classic synthesis, namely compound purification, and pairs it with high-throughput, semi-automated plate-based synthesis, and direct cellular assay evaluation. We applied this direct-to-biology approach to four diverse targets, demonstrating the general applicability of this technology. PROTAC synthesis was realized by using the highly efficient copper-catalyzed azide-alkyne cycloaddition reaction. This simplified reaction setup enabled synthesis in the nanomole scale with reaction volumes as low as 5 μL. The high-throughput strategy allows hundreds of PROTACs to be synthesized and evaluated within a few days, facilitating comprehensive assessment of target degradability, rapid hit identification, and selection of the most suitable E3 ligase for degrader development.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"275 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146021542","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：