Hepatic fibrosis represents a major global public health challenge, yet effective therapeutic interventions remain limited. In this study, we synthesized 40 derivatives through systematic structural modification of l-theanine and identified compound 9a was a potent antifibrotic agent. In vitro experiments revealed that compound 9a dose-dependently inhibited TGFβ1-induced activation of hepatic stellate cells (LX-2 and mHSC). Moreover, in both rat bile duct ligation (BDL) and mouse methionine-choline-deficient high-fat diet (CDAHFD) induced liver fibrosis models, compound 9a significantly attenuated hepatic injury, fibrosis, and inflammation, demonstrating robust hepatoprotective effects. Mechanistic investigations showed that compound 9a directly interacts with Cathepsin D and promotes its degradation, thereby suppressing the expression of fibrogenic and inflammatory genes. Pharmacokinetic studies demonstrated that compound 9a undergoes metabolic conversion to yield pharmacologically active metabolites 10 and 11c. Collectively, these results highlight compound 9a as a promising l-theanine-based candidate for the treatment of hepatic fibrosis.
{"title":"Design, Synthesis, and Mechanistic Evaluation of l-Theanine Derivatives Targeting Cathepsin D for Anti-Hepatic Fibrosis","authors":"Miao Lv,Simin Guo,Congying Huang,Zhenning Lu,Yiming Li,Yang Li,Yichen Liu,Hongwei He,Yang Hexian,Na Zhang,Zhuorong Li","doi":"10.1021/acs.jmedchem.5c03096","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03096","url":null,"abstract":"Hepatic fibrosis represents a major global public health challenge, yet effective therapeutic interventions remain limited. In this study, we synthesized 40 derivatives through systematic structural modification of l-theanine and identified compound 9a was a potent antifibrotic agent. In vitro experiments revealed that compound 9a dose-dependently inhibited TGFβ1-induced activation of hepatic stellate cells (LX-2 and mHSC). Moreover, in both rat bile duct ligation (BDL) and mouse methionine-choline-deficient high-fat diet (CDAHFD) induced liver fibrosis models, compound 9a significantly attenuated hepatic injury, fibrosis, and inflammation, demonstrating robust hepatoprotective effects. Mechanistic investigations showed that compound 9a directly interacts with Cathepsin D and promotes its degradation, thereby suppressing the expression of fibrogenic and inflammatory genes. Pharmacokinetic studies demonstrated that compound 9a undergoes metabolic conversion to yield pharmacologically active metabolites 10 and 11c. Collectively, these results highlight compound 9a as a promising l-theanine-based candidate for the treatment of hepatic fibrosis.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"295 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146138915","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 : 2026-02-09DOI: 10.1021/acs.jmedchem.5c02984
Ángel García de Lucas,Negar A. Samani,Olli Moisio,Luciana Kovacs,Risto Savela,Sanna L. Soini,Sami Oksanen,Jatta S. Helin,Johan Rajander,Anu J. Airaksinen,Urpo Lamminmäki,Francisco López-Picón
Gamma-aminobutyric acid type A (GABA-A) receptors are the principal inhibitory neurotransmitter receptors in the central nervous system (CNS), but their functions in the peripheral nervous system (PNS) and organs such as the heart remain poorly understood. These receptors comprise various subtypes based on subunit composition with differential brain and heart expression linked to distinct pathologies. Current positron emission tomography (PET) imaging protocols use radioligands lacking subtype specificity. To address this, we developed a PET tracer targeting the α1 subunit. The α1-specific single-chain variable fragment (scFv) 1F4 was engineered from the variable domains of monoclonal antibody (mAb) 1F4. It was efficiently 18F-labeled under mild conditions via biorthogonal inverse electron demand Diels–Alder (iEDDA) ligation. PET biodistribution in mice showed favorable pharmacokinetics for [18F]F-Tz-TCO-scFv 1F4 with specific α1 subunit binding in the brain, heart, and lungs. This tracer promises to evaluate GABA-A α1 distribution and expression in peripheral organs, particularly the heart.
{"title":"Fluorine-18 Radiolabeled Single-Chain Antibody Variable Fragment 1F4 Targets α1-Subunit Gamma-Aminobutyric Acid Type A Receptors in Mice","authors":"Ángel García de\u0000Lucas,Negar A. Samani,Olli Moisio,Luciana Kovacs,Risto Savela,Sanna L. Soini,Sami Oksanen,Jatta S. Helin,Johan Rajander,Anu J. Airaksinen,Urpo Lamminmäki,Francisco López-Picón","doi":"10.1021/acs.jmedchem.5c02984","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02984","url":null,"abstract":"Gamma-aminobutyric acid type A (GABA-A) receptors are the principal inhibitory neurotransmitter receptors in the central nervous system (CNS), but their functions in the peripheral nervous system (PNS) and organs such as the heart remain poorly understood. These receptors comprise various subtypes based on subunit composition with differential brain and heart expression linked to distinct pathologies. Current positron emission tomography (PET) imaging protocols use radioligands lacking subtype specificity. To address this, we developed a PET tracer targeting the α1 subunit. The α1-specific single-chain variable fragment (scFv) 1F4 was engineered from the variable domains of monoclonal antibody (mAb) 1F4. It was efficiently 18F-labeled under mild conditions via biorthogonal inverse electron demand Diels–Alder (iEDDA) ligation. PET biodistribution in mice showed favorable pharmacokinetics for [18F]F-Tz-TCO-scFv 1F4 with specific α1 subunit binding in the brain, heart, and lungs. This tracer promises to evaluate GABA-A α1 distribution and expression in peripheral organs, particularly the heart.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"70 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146138911","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 : 2026-02-08DOI: 10.1021/acs.jmedchem.5c03208
James Neef,Kimberly S. Straley,Chinmoy Mukherjee,Amol Tipnis,Suleman Riyajsaheb Maujan,Maulasri Bhatta,Sambad Sharma,Sara Sinicropi-Yao,Joe DeBartolo,Andrew J. McRiner,Betty Chan,Henry Wilson,Christina S. Lee,Zied Boudhraa,Mohamed El Ezzy,Mark Bittinger,Laura Jennings Antipov,Thomas G. Graeber,Katharine E. Yen,David S. Millan
Using our proprietary AI/ML platform AURIGIN that maps tumor cells against normal developmental pathways, we identify targets that have been hijacked by cancerous cells to maintain a highly plastic proliferative cell state. We identified the histone acetyltransferase KAT2A as a key driver of tumor cell plasticity in a subset of acute myeloid leukemias (AML) and neuroendocrine carcinomas such as small cell lung cancer (SCLC) and neuroendocrine prostate cancer (NEPC). Herein, we describe our development of heterobifunctional degraders of KAT2A/B, resulting in compound 7, a picomolar degrader that is capable of inhibiting proliferation of AML (MOLM-13) and SCLC (NCI–H1048) cell lines in vitro and demonstrates robust degradation of KAT2A in NCI–H1048 engrafted mice when administered IP. Building on the success of compound 7, we subsequently developed orally bioavailable degraders of KAT2A/B, exemplified by compound 24, that achieved an oral bioavailability of 47% in mice.
{"title":"Discovery and Optimization of Orally Bioavailable Heterobifunctional Degraders of KAT2A/B for the Treatment of Cancer","authors":"James Neef,Kimberly S. Straley,Chinmoy Mukherjee,Amol Tipnis,Suleman Riyajsaheb Maujan,Maulasri Bhatta,Sambad Sharma,Sara Sinicropi-Yao,Joe DeBartolo,Andrew J. McRiner,Betty Chan,Henry Wilson,Christina S. Lee,Zied Boudhraa,Mohamed El Ezzy,Mark Bittinger,Laura Jennings Antipov,Thomas G. Graeber,Katharine E. Yen,David S. Millan","doi":"10.1021/acs.jmedchem.5c03208","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03208","url":null,"abstract":"Using our proprietary AI/ML platform AURIGIN that maps tumor cells against normal developmental pathways, we identify targets that have been hijacked by cancerous cells to maintain a highly plastic proliferative cell state. We identified the histone acetyltransferase KAT2A as a key driver of tumor cell plasticity in a subset of acute myeloid leukemias (AML) and neuroendocrine carcinomas such as small cell lung cancer (SCLC) and neuroendocrine prostate cancer (NEPC). Herein, we describe our development of heterobifunctional degraders of KAT2A/B, resulting in compound 7, a picomolar degrader that is capable of inhibiting proliferation of AML (MOLM-13) and SCLC (NCI–H1048) cell lines in vitro and demonstrates robust degradation of KAT2A in NCI–H1048 engrafted mice when administered IP. Building on the success of compound 7, we subsequently developed orally bioavailable degraders of KAT2A/B, exemplified by compound 24, that achieved an oral bioavailability of 47% in mice.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"5 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146138913","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 : 2026-02-08DOI: 10.1021/acs.jmedchem.5c03639
Jinyuan Wu,Sining Tao,An-chao Ge,Zhongxia Zhou,Dongwei Kang,Xinyong Liu
The family Paramyxoviridae comprises nonsegmented, negative-sense RNA viruses (nsNSV), including key pathogens like Nipah, measles, and parainfluenza viruses. The lack of approved specific therapeutics against paramyxoviruses, alongside concerns such as vaccine hesitancy and reduced efficacy for certain existing vaccines, presents a major challenge to global public health. There is an urgent need to develop broad-spectrum antiviral drugs, and the paramyxovirus polymerase complex has emerged as an ideal target owing to its conservation, specificity, and essential role in the viral life cycle. This Perspective synthesizes recent structural biology studies of various paramyxovirus polymerase complexes, discusses their commonalities and distinct features, and analyzes the mechanisms of existing inhibitors. We identify potential druggable sites and propose rational drug design strategies. It is expected that this work will serve as a valuable reference for advancing the development of related therapeutic interventions.
{"title":"Research Progress on the Structural Biology of Paramyxovirus Polymerase and Its Inhibitors","authors":"Jinyuan Wu,Sining Tao,An-chao Ge,Zhongxia Zhou,Dongwei Kang,Xinyong Liu","doi":"10.1021/acs.jmedchem.5c03639","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03639","url":null,"abstract":"The family Paramyxoviridae comprises nonsegmented, negative-sense RNA viruses (nsNSV), including key pathogens like Nipah, measles, and parainfluenza viruses. The lack of approved specific therapeutics against paramyxoviruses, alongside concerns such as vaccine hesitancy and reduced efficacy for certain existing vaccines, presents a major challenge to global public health. There is an urgent need to develop broad-spectrum antiviral drugs, and the paramyxovirus polymerase complex has emerged as an ideal target owing to its conservation, specificity, and essential role in the viral life cycle. This Perspective synthesizes recent structural biology studies of various paramyxovirus polymerase complexes, discusses their commonalities and distinct features, and analyzes the mechanisms of existing inhibitors. We identify potential druggable sites and propose rational drug design strategies. It is expected that this work will serve as a valuable reference for advancing the development of related therapeutic interventions.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"244 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146138916","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}
IRAK4 plays a pivotal role in autoimmune diseases by exerting both kinase and scaffolding functions. Conventional inhibitors of IRAK4 target its kinase activity while leaving the scaffolding function intact. PROTACs, which induce the complete degradation of target proteins, offer a promising strategy to overcome the constraints of traditional inhibition. Here, we designed and synthesized a series of nucleolin (NCL)-bridged, MDM2-recruiting PROTAC degraders by conjugating oridonin (Ori) with Zimlovisertib (Zim). Structure–activity relationship studies identified Ori-Zim-6 as the most potent degrader. Mechanistic investigations revealed that Ori-Zim-6 triggered the proteasomal degradation of IRAK4. Ori-Zim-6 effectively inhibited pro-inflammatory response across multiple cell types in vitro. In a mouse model of psoriasis, oral administration of Ori-Zim-6 resulted in robust therapeutic efficacy and a favorable safety profile. Notably, Ori-Zim-6 exhibited superior anti-inflammatory activity compared to the reference degrader KT-474. These findings establish Ori-Zim-6 as an orally available IRAK4 degrader for the treatment of autoimmune diseases.
{"title":"Design, Synthesis, and Evaluation of Nucleolin-Bridged, MDM2-Recruiting IRAK4 Degraders for the Treatment of Autoimmune Diseases","authors":"Ziting Feng,Xiaoxuan Zhang,Yi Ding,Kang Zhang,Fang Qiu,Duoli Xie,Aiping Lu,Lingqiang Zhang,Chao Liang","doi":"10.1021/acs.jmedchem.5c03507","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03507","url":null,"abstract":"IRAK4 plays a pivotal role in autoimmune diseases by exerting both kinase and scaffolding functions. Conventional inhibitors of IRAK4 target its kinase activity while leaving the scaffolding function intact. PROTACs, which induce the complete degradation of target proteins, offer a promising strategy to overcome the constraints of traditional inhibition. Here, we designed and synthesized a series of nucleolin (NCL)-bridged, MDM2-recruiting PROTAC degraders by conjugating oridonin (Ori) with Zimlovisertib (Zim). Structure–activity relationship studies identified Ori-Zim-6 as the most potent degrader. Mechanistic investigations revealed that Ori-Zim-6 triggered the proteasomal degradation of IRAK4. Ori-Zim-6 effectively inhibited pro-inflammatory response across multiple cell types in vitro. In a mouse model of psoriasis, oral administration of Ori-Zim-6 resulted in robust therapeutic efficacy and a favorable safety profile. Notably, Ori-Zim-6 exhibited superior anti-inflammatory activity compared to the reference degrader KT-474. These findings establish Ori-Zim-6 as an orally available IRAK4 degrader for the treatment of autoimmune diseases.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"132 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146138914","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}
Heparin is among the most widely used anticoagulants worldwide, with an annual market of ∼$4 billion. It also poses potential bleeding risks (0.5–5%), occasionally life-threatening, necessitating heparin reversal agents. Protamine sulfate is the only approved agent to reverse heparin for overdose, bleeding, cardiopulmonary bypass, or urgent surgical intervention. However, its efficacy is limited against low-molecular-weight heparin (LMWH) and negligible against ultralow-molecular-weight heparin (ULMWH). Additional concerns include allergic reactions, hypotension, and sourcing constraints, underscoring the need for safe and effective alternatives. In recent years, diverse novel heparin reversal agents have emerged, spanning proteins/peptides, cationic macromolecules, nanoparticles, gels, and small molecules, yet a medicinal-chemistry-oriented analysis of these agents remains lacking. In this perspective, we critically summarize design strategies, structural features, and biological activities of reported heparin reversal agents, and discuss key challenges and future directions to inform the development of novel antidotes.
{"title":"Advances in Heparin Reversal Agents: Design Strategies, Structural Features, and Pharmacological Insights","authors":"Wenhui Zhang,Callum Stewart,Aohua Xiao,Yunzhen Zhan,Tianyi Wei,Jiayu Wu,Linxian Li,Canhui Zheng,Hui Huang,Jinsong Han","doi":"10.1021/acs.jmedchem.5c02439","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02439","url":null,"abstract":"Heparin is among the most widely used anticoagulants worldwide, with an annual market of ∼$4 billion. It also poses potential bleeding risks (0.5–5%), occasionally life-threatening, necessitating heparin reversal agents. Protamine sulfate is the only approved agent to reverse heparin for overdose, bleeding, cardiopulmonary bypass, or urgent surgical intervention. However, its efficacy is limited against low-molecular-weight heparin (LMWH) and negligible against ultralow-molecular-weight heparin (ULMWH). Additional concerns include allergic reactions, hypotension, and sourcing constraints, underscoring the need for safe and effective alternatives. In recent years, diverse novel heparin reversal agents have emerged, spanning proteins/peptides, cationic macromolecules, nanoparticles, gels, and small molecules, yet a medicinal-chemistry-oriented analysis of these agents remains lacking. In this perspective, we critically summarize design strategies, structural features, and biological activities of reported heparin reversal agents, and discuss key challenges and future directions to inform the development of novel antidotes.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"35 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146138912","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 : 2026-02-07DOI: 10.1021/acs.jmedchem.5c01766
Polina Ilina, Vladimir Iashin, Cristina D Cruz, Juho Heininen, Iiro Järvi, Inna Pönniö, Sami Heikkinen, Pauli Johan Wrigstedt, Leo Ghemtio, Karina Moslova, Henri Xhaard, Paula Kiuru, Jesús Perea-Buceta, Päivi Tammela
In this study, we investigated the potential of diazaborine compounds for antibacterial drug development. Most promising diazaborines demonstrated activity against several Gram-negative pathogens including Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Salmonella enterica ser. Typhimurium. For a subset of diazaborines, we showed inhibitory activity against isolated FabI (enoyl-acyl carrier protein reductase) enzyme aligning with antimicrobial activity, suggesting a mechanism of action via the FabI enzyme and providing early information on structure-activity relationships. Optimized diazaborine scaffold 11 features an amino group in a meta-relative position to the sulfonamide group and exhibited the most favorable bioactivity profile, showing MIC of 6.25 μM against E. coli, low cytotoxicity, and high stability in human plasma. Furthermore, diazaborine 11 had synergistic effect with colistin (FICI 0.25) and preliminary data show that it may rescue Galleria mellonella larvae from lethal E. coli infection at the therapeutic dose of 1.13 and 2.81 mg/kg, demonstrating efficacy similar to ciprofloxacin.
{"title":"Rediscovering Diazaborines: Synthesis and Bioactivity Profiling of Boron-Containing FabI Inhibitors against Gram-Negative Bacteria.","authors":"Polina Ilina, Vladimir Iashin, Cristina D Cruz, Juho Heininen, Iiro Järvi, Inna Pönniö, Sami Heikkinen, Pauli Johan Wrigstedt, Leo Ghemtio, Karina Moslova, Henri Xhaard, Paula Kiuru, Jesús Perea-Buceta, Päivi Tammela","doi":"10.1021/acs.jmedchem.5c01766","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01766","url":null,"abstract":"<p><p>In this study, we investigated the potential of diazaborine compounds for antibacterial drug development. Most promising diazaborines demonstrated activity against several Gram-negative pathogens including <i>Escherichia coli</i>, <i>Klebsiella pneumoniae</i>, <i>Acinetobacter baumannii</i>, and <i>Salmonella enterica</i> ser. Typhimurium. For a subset of diazaborines, we showed inhibitory activity against isolated FabI (enoyl-acyl carrier protein reductase) enzyme aligning with antimicrobial activity, suggesting a mechanism of action via the FabI enzyme and providing early information on structure-activity relationships. Optimized diazaborine scaffold <b>11</b> features an amino group in a meta-relative position to the sulfonamide group and exhibited the most favorable bioactivity profile, showing MIC of 6.25 μM against <i>E. coli</i>, low cytotoxicity, and high stability in human plasma. Furthermore, diazaborine <b>11</b> had synergistic effect with colistin (FICI 0.25) and preliminary data show that it may rescue <i>Galleria mellonella</i> larvae from lethal <i>E. coli</i> infection at the therapeutic dose of 1.13 and 2.81 mg/kg, demonstrating efficacy similar to ciprofloxacin.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146130585","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}
Hepatocellular carcinoma (HCC) poses significant clinical challenges, including high recurrence, mortality, and drug resistance, underscoring the urgent needs for novel targeted therapies. Lin28B, an RNA-binding protein frequently overexpressed in HCC, promotes tumor progression by enhancing oncogenic signaling pathways and inhibiting the maturation of tumor-suppressive let-7 family miRNAs. However, due to the lack of conventional small-molecule binding pockets, Lin28B has long been considered an undruggable target. In this study, a series of pre-let-7-PROTACs were constructed by conjugating pre-let-7 family miRNAs and E3 ligase ligands. Most pre-let-7-PROTACs achieved efficient and specific degradation of Lin28B and restored endogenous mature let-7 expression, thereby suppressing HCC cell proliferation and migration, promoting apoptosis, and enhancing chemosensitivity. In a Huh-7 xenograft tumor model, pre-let-7-PROTACs exhibited significant synergistic antitumor effects when combined with sorafenib (SFB). This study confirmed that pre-let-7-PROTACs reduce tumor stemness by degrading Lin28B, offering a promising therapeutic approach for HCC.
{"title":"Targeted Degradation of Lin28B Using Pre-let-7-PROTACs for Hepatocellular Carcinoma Therapy.","authors":"Jianfei Xu, Xingxing Liang, Zhaopeng Yan, Yuejie Zhu, Jing Wang, Qian Wang, Zhenjun Yang, Xinjing Tang","doi":"10.1021/acs.jmedchem.5c03203","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03203","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) poses significant clinical challenges, including high recurrence, mortality, and drug resistance, underscoring the urgent needs for novel targeted therapies. Lin28B, an RNA-binding protein frequently overexpressed in HCC, promotes tumor progression by enhancing oncogenic signaling pathways and inhibiting the maturation of tumor-suppressive let-7 family miRNAs. However, due to the lack of conventional small-molecule binding pockets, Lin28B has long been considered an undruggable target. In this study, a series of pre-let-7-PROTACs were constructed by conjugating pre-let-7 family miRNAs and E3 ligase ligands. Most pre-let-7-PROTACs achieved efficient and specific degradation of Lin28B and restored endogenous mature let-7 expression, thereby suppressing HCC cell proliferation and migration, promoting apoptosis, and enhancing chemosensitivity. In a Huh-7 xenograft tumor model, pre-let-7-PROTACs exhibited significant synergistic antitumor effects when combined with sorafenib (SFB). This study confirmed that pre-let-7-PROTACs reduce tumor stemness by degrading Lin28B, offering a promising therapeutic approach for HCC.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146130524","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}
CBP/p300 and BRD4 synergistically drive prostate cancer progression. Here, we report the rational design, synthesis, and biological evaluation of novel PROTACs capable of simultaneously degrading CBP/p300 and BRD4. The representative compounds 10h and 29c induced robust degradation of both targets with DC50 values ranging from 8.8 pM to 10.5 nM in PC-3 prostate cancer cells, accompanied by marked downregulation of c-Myc and acetylated H3K27. Both compounds displayed potent antiproliferative activity across multiple cancer cell lines, with higher potency than NEO2734, paclitaxel (PTX), and ARV-771. In a PC-3 xenograft mouse model, compound 29c achieved dose-dependent tumor growth inhibition (TGI) of up to 81.5% at a low dose of 0.2 mg/kg, administered every other day, significantly surpassing the efficacy of NEO2734 and PTX at higher doses. Together, 29c, a highly efficient CBP/p300 and BRD4 dual-target degrader, demonstrates significant therapeutic potential in prostate cancer and warrants further development.
{"title":"Discovery of Novel CBP/p300 and BRD4 Dual-Target PROTACs with Potent Antitumor Activity in Prostate Cancer.","authors":"Yi-Zhe Zhang, Hui-Juan Zhu, Xiao-Xiao Zhou, Shi-Jie Li, Di Han, Feng-Xiang Liu, Hui-Min Zhou, Xin-Yu Jiang, Yuan-Yuan Guan, Hui-Ru Ren, Ying Wang, Wen-Jing Dai, Yi-Bo Ban, Nan Su, Yong-Cheng Ma, Yong-Tao Xu, Sai-Qi Wang, Ying-Chao Duan","doi":"10.1021/acs.jmedchem.5c03168","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03168","url":null,"abstract":"<p><p>CBP/p300 and BRD4 synergistically drive prostate cancer progression. Here, we report the rational design, synthesis, and biological evaluation of novel PROTACs capable of simultaneously degrading CBP/p300 and BRD4. The representative compounds <b>10h</b> and <b>29c</b> induced robust degradation of both targets with DC<sub>50</sub> values ranging from 8.8 pM to 10.5 nM in PC-3 prostate cancer cells, accompanied by marked downregulation of c-Myc and acetylated H3K27. Both compounds displayed potent antiproliferative activity across multiple cancer cell lines, with higher potency than NEO2734, paclitaxel (PTX), and ARV-771. In a PC-3 xenograft mouse model, compound <b>29c</b> achieved dose-dependent tumor growth inhibition (TGI) of up to 81.5% at a low dose of 0.2 mg/kg, administered every other day, significantly surpassing the efficacy of NEO2734 and PTX at higher doses. Together, <b>29c</b>, a highly efficient CBP/p300 and BRD4 dual-target degrader, demonstrates significant therapeutic potential in prostate cancer and warrants further development.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146130529","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 : 2026-02-06DOI: 10.1021/acs.jmedchem.5c02607
Eduardo J. Martinez, Darren H. Wong, Amish J. Patel, Roy J. Vaz, Robert W. Busby, Robert Zahler, Daniel Schefer, Hui Zhao, Xiaoming Xu, Zizhao Liu, Ruifang Meng, Bernd Kaiser, Jianchao Liu, Lei Wen, Rui Liu, Katya Leites, Helen S. Tian, Sohail F. Tavazoie, Masoud F. Tavazoie, Isabel Kurth
Creatine, a naturally occurring guanidine carboxylic acid, serves as a critical energy metabolite in tissues with high energy demands. Certain cancers upregulate creatine metabolism to supplement their energy needs. Ompenaclid, a salt form of the well-studied creatine transporter inhibitor 3-guanidinopropionic acid (β-GPA), is in clinical development for the treatment of patients with colorectal tumors. Existing SLC6A8 inhibitors are low-potency molecules and frequently interact with related transporters. Herein, we report the discovery of SLC6A8 inhibitors with increased selectivity as well as in vitro and in vivo potency. A bioisostere approach was used by replacing the carboxylic acid of β-GPA with surrogate functional groups to achieve these improvements. Docking of these inhibitors into the recently published SLC6A8 cryo-EM structure reveals key binding contacts and supports the observed structure–activity relationships.
{"title":"Carboxylic Acid Bioisosteres of Creatine as Novel and Selective Substrate Competitive Inhibitors of the Creatine Transporter SLC6A8","authors":"Eduardo J. Martinez, Darren H. Wong, Amish J. Patel, Roy J. Vaz, Robert W. Busby, Robert Zahler, Daniel Schefer, Hui Zhao, Xiaoming Xu, Zizhao Liu, Ruifang Meng, Bernd Kaiser, Jianchao Liu, Lei Wen, Rui Liu, Katya Leites, Helen S. Tian, Sohail F. Tavazoie, Masoud F. Tavazoie, Isabel Kurth","doi":"10.1021/acs.jmedchem.5c02607","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02607","url":null,"abstract":"Creatine, a naturally occurring guanidine carboxylic acid, serves as a critical energy metabolite in tissues with high energy demands. Certain cancers upregulate creatine metabolism to supplement their energy needs. Ompenaclid, a salt form of the well-studied creatine transporter inhibitor 3-guanidinopropionic acid (β-GPA), is in clinical development for the treatment of patients with colorectal tumors. Existing SLC6A8 inhibitors are low-potency molecules and frequently interact with related transporters. Herein, we report the discovery of SLC6A8 inhibitors with increased selectivity as well as <i>in vitro</i> and <i>in vivo</i> potency. A bioisostere approach was used by replacing the carboxylic acid of β-GPA with surrogate functional groups to achieve these improvements. Docking of these inhibitors into the recently published SLC6A8 cryo-EM structure reveals key binding contacts and supports the observed structure–activity relationships.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"12 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122289","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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