Pub Date : 2026-10-12DOI: 10.1021/acs.jmedchem.6c01002
Shaowen Cai,Furui Shi,Jiayi Chen,Min Yu,Zhixian Shi,Hairong Tang,Yang Wang
In this work, a series of novel dual inhibitors against both tubulin and histone deacetylase (HDAC) were designed and synthesized by integrating the natural product Millepachine with the key pharmacophore of HDAC inhibitors. Among them, compound 6 exhibited potent antiproliferative activity against 12 cancer cell lines, with IC50 values ranging from 0.020 to 0.244 μM. Mechanistic investigations revealed that compound 6 inhibited both tubulin polymerization (IC50 2.0 μM) and HDAC8 (IC50 0.110 μM), with 54-, 27- and 132-fold selectivity over HDAC1, HDAC4 and HDAC6, respectively. In an ovarian cancer xenograft mouse model, compound 6 exhibited significant inhibitory effect on tumor growth with a favorable safety profile. These findings identify compound 6 as a promising tubulin/HDAC8 dual inhibitor for further investigation.
{"title":"Discovery of a Novel Dual Inhibitor Targeting Tubulin and Histone Deacetylase 8 for Treatment of the Ovarian Cancer","authors":"Shaowen Cai,Furui Shi,Jiayi Chen,Min Yu,Zhixian Shi,Hairong Tang,Yang Wang","doi":"10.1021/acs.jmedchem.6c01002","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01002","url":null,"abstract":"In this work, a series of novel dual inhibitors against both tubulin and histone deacetylase (HDAC) were designed and synthesized by integrating the natural product Millepachine with the key pharmacophore of HDAC inhibitors. Among them, compound 6 exhibited potent antiproliferative activity against 12 cancer cell lines, with IC50 values ranging from 0.020 to 0.244 μM. Mechanistic investigations revealed that compound 6 inhibited both tubulin polymerization (IC50 2.0 μM) and HDAC8 (IC50 0.110 μM), with 54-, 27- and 132-fold selectivity over HDAC1, HDAC4 and HDAC6, respectively. In an ovarian cancer xenograft mouse model, compound 6 exhibited significant inhibitory effect on tumor growth with a favorable safety profile. These findings identify compound 6 as a promising tubulin/HDAC8 dual inhibitor for further investigation.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"1 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152169","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 : 2026-10-12DOI: 10.1021/acs.jmedchem.6c02353
Giulia Greco,Giulia Giugliano,Alessia Marconi,Paolo Emidio Costantini,Michele Trivini,Giulia Neggiani,Francesca Maffei,Manuele Di Sante,Tainah Dorina Marforio,Alessandro Calza,Manuela Sollazzo,Anna Maria Porcelli,Giuseppe Gasparre,Francesco Zerbetto,Alberto Danielli,Julia Westermayr,Matteo Di Giosia,Carmela Fimognari,Eleonora Turrini,Edoardo Jun Mattioli,Matteo Calvaresi
Chemophototherapy (CPT), combining chemotherapy and photodynamic therapy (PDT), is a promising strategy to enhance anticancer efficacy while reducing systemic toxicity. Many approved drugs contain chromophoric moieties that absorb visible light, suggesting their potential as intrinsic photosensitizers. Herein, we introduce a single-molecule chemophototherapy (SM-CPT) approach based on computational screening of approved anticancer drugs for repurposing as photosensitizers. A curated library of 238 small-molecule drugs was screened using time-dependent density functional theory to identify compounds with favourable photophysical properties. Fifteen candidates were identified, and mitoxantrone, pixantrone, daunorubicin, and epirubicin were selected for experimental validation. All compounds generated reactive oxygen species upon irradiation and showed enhanced cytotoxicity in breast cancer cell models, with up to an order-of-magnitude reduction in half-maximal inhibitory concentration values. The approach was further validated in ovarian cancer models, including platinum-resistant cells and patient-derived ascites, highlighting SM-CPT as a translationally attractive light-activated cancer therapy.
{"title":"Repurposing Approved Chemotherapeutics as Intrinsic Photosensitizers for Single-Molecule Chemophototherapy","authors":"Giulia Greco,Giulia Giugliano,Alessia Marconi,Paolo Emidio Costantini,Michele Trivini,Giulia Neggiani,Francesca Maffei,Manuele Di Sante,Tainah Dorina Marforio,Alessandro Calza,Manuela Sollazzo,Anna Maria Porcelli,Giuseppe Gasparre,Francesco Zerbetto,Alberto Danielli,Julia Westermayr,Matteo Di Giosia,Carmela Fimognari,Eleonora Turrini,Edoardo Jun Mattioli,Matteo Calvaresi","doi":"10.1021/acs.jmedchem.6c02353","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02353","url":null,"abstract":"Chemophototherapy (CPT), combining chemotherapy and photodynamic therapy (PDT), is a promising strategy to enhance anticancer efficacy while reducing systemic toxicity. Many approved drugs contain chromophoric moieties that absorb visible light, suggesting their potential as intrinsic photosensitizers. Herein, we introduce a single-molecule chemophototherapy (SM-CPT) approach based on computational screening of approved anticancer drugs for repurposing as photosensitizers. A curated library of 238 small-molecule drugs was screened using time-dependent density functional theory to identify compounds with favourable photophysical properties. Fifteen candidates were identified, and mitoxantrone, pixantrone, daunorubicin, and epirubicin were selected for experimental validation. All compounds generated reactive oxygen species upon irradiation and showed enhanced cytotoxicity in breast cancer cell models, with up to an order-of-magnitude reduction in half-maximal inhibitory concentration values. The approach was further validated in ovarian cancer models, including platinum-resistant cells and patient-derived ascites, highlighting SM-CPT as a translationally attractive light-activated cancer therapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"53 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152168","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 : 2026-10-12DOI: 10.1021/acs.jmedchem.6c01103
Wenjuan Li,Shanhe Li,Zhongzhao Li,Gang Xu,Guochao Li,Zhenlei Zhang,Hong Liang,Feng Yang
Triple-negative breast cancer (TNBC) remains challenging due to its aggressiveness and the lack of targeted therapies. In this study, we proposed designing a ferric (Fe) agent based on human serum albumin (HSA) for chemodynamic therapy-driven synergistic therapy. To this end, we not only optimized a series of Fe(III) compounds to obtain Fe4, which has remarkable toxicity against TNBC cells, but we also constructed the HSA-Fe4 NPs delivery system. Structural analysis revealed that Fe4 binds within the IB subdomain of HSA, with His-146 coordinating the iron center. Importantly, Fe4/HSA-Fe4 NPs significantly suppressed the metastasis and growth of TNBC in vivo. Moreover, we elucidated the mechanisms by which Fe4/HSA-Fe4 NPs inhibited the growth and metastasis of TNBC: inducing Fenton reaction-mediated chemodynamic therapy, inducing ferroptosis, and tri-activating the immune response through the activation of the cGAS-STING pathway, the induction of immunogenic cell death, and the repolarization of M2 macrophages.
{"title":"Developing a Ferric(III) Agent for Targeted Inhibition of Growth and Metastasis of Triple-Negative Breast Cancer Based on Human Serum Albumin by Chemodynamic Therapy-Driven Synergistic Therapy","authors":"Wenjuan Li,Shanhe Li,Zhongzhao Li,Gang Xu,Guochao Li,Zhenlei Zhang,Hong Liang,Feng Yang","doi":"10.1021/acs.jmedchem.6c01103","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01103","url":null,"abstract":"Triple-negative breast cancer (TNBC) remains challenging due to its aggressiveness and the lack of targeted therapies. In this study, we proposed designing a ferric (Fe) agent based on human serum albumin (HSA) for chemodynamic therapy-driven synergistic therapy. To this end, we not only optimized a series of Fe(III) compounds to obtain Fe4, which has remarkable toxicity against TNBC cells, but we also constructed the HSA-Fe4 NPs delivery system. Structural analysis revealed that Fe4 binds within the IB subdomain of HSA, with His-146 coordinating the iron center. Importantly, Fe4/HSA-Fe4 NPs significantly suppressed the metastasis and growth of TNBC in vivo. Moreover, we elucidated the mechanisms by which Fe4/HSA-Fe4 NPs inhibited the growth and metastasis of TNBC: inducing Fenton reaction-mediated chemodynamic therapy, inducing ferroptosis, and tri-activating the immune response through the activation of the cGAS-STING pathway, the induction of immunogenic cell death, and the repolarization of M2 macrophages.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"29 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152138","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 : 2026-10-12DOI: 10.1021/acs.jmedchem.6c01530
Vladislav Lobanov,Andréanne Lupien,Anthony Vocat,Rajkumar Singh,Alexander Lepioshkin,Natalia Monakhova,Olga Riabova,Maria G. Khrenova,Stewart T. Cole,Vadim Makarov
Pulmonary tuberculosis remains one of the most prevalent and threatening infectious diseases. Classical anti-tubercular therapy targets essential enzymes of the pathogen Mycobacterium tuberculosis (Mtb), thereby suppressing bacterial growth. However, the emergence of drug-resistant strains necessitates alternative therapeutic approaches. Virulence inhibition is a promising strategy that blocks Mtb virulence factors required for survival within host cells. We previously identified a hit compound, BTP15, which protected fibroblasts and THP-1 macrophages from Mtb-induced cell death ex vivo by blocking phagosomal escape through inhibition of the mycobacterial histidine kinase MprB. Due to poor pharmacokinetics, the structure of BTP15 was optimized. New benzothiophene derivatives were screened for MprB inhibition, microsomal stability, toxicity, and ex vivo efficacy in THP-1 and MRC-5 cells. The lead compound, 7a, exhibited favorable pharmacokinetic parameters, showed no toxicity in mice at 250 mg/kg, and prevented Mtb dissemination in an acute mouse model of tuberculosis.
{"title":"Antivirulence Benzothiophenes Inhibit Intracellular Mycobacterium tuberculosis by Targeting the Sensor Histidine Kinase MprB","authors":"Vladislav Lobanov,Andréanne Lupien,Anthony Vocat,Rajkumar Singh,Alexander Lepioshkin,Natalia Monakhova,Olga Riabova,Maria G. Khrenova,Stewart T. Cole,Vadim Makarov","doi":"10.1021/acs.jmedchem.6c01530","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01530","url":null,"abstract":"Pulmonary tuberculosis remains one of the most prevalent and threatening infectious diseases. Classical anti-tubercular therapy targets essential enzymes of the pathogen Mycobacterium tuberculosis (Mtb), thereby suppressing bacterial growth. However, the emergence of drug-resistant strains necessitates alternative therapeutic approaches. Virulence inhibition is a promising strategy that blocks Mtb virulence factors required for survival within host cells. We previously identified a hit compound, BTP15, which protected fibroblasts and THP-1 macrophages from Mtb-induced cell death ex vivo by blocking phagosomal escape through inhibition of the mycobacterial histidine kinase MprB. Due to poor pharmacokinetics, the structure of BTP15 was optimized. New benzothiophene derivatives were screened for MprB inhibition, microsomal stability, toxicity, and ex vivo efficacy in THP-1 and MRC-5 cells. The lead compound, 7a, exhibited favorable pharmacokinetic parameters, showed no toxicity in mice at 250 mg/kg, and prevented Mtb dissemination in an acute mouse model of tuberculosis.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"59 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152137","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}
Local anesthetics (LAs), a type of substance with the ability of blocking nerve fiber conduction, are indispensable in clinical practice for pain relief. However, the duration of action and sensory-motor nerve selectivity of conventional LAs require further optimization. Herein, we wish to report the discovery of novel ammonium salts derived from natural cinchona alkaloids for long-acting and sensory-selective nerve blockades. The bicyclic quincoridine skeleton exhibited superior nerve blockade efficacy compared to acyclic and monocyclic analogs. Compound CLA-1-3 produced prolonged nerve blockade (over 50 h) in the rat sciatic nerve block model, possessing an IC50 value of approximately 0.39 μmol/L for voltage-gated sodium channel inhibition. On the other hand, at a concentration range of 0.30% to 0.60%, compound CLA-3-5 achieved sensory-selective nerve blockade lasting up to 3 h. The candidate molecules and underlying mechanistic insights will be valuable assets for drug development and therapeutic innovation.
{"title":"Cinchona Alkaloids-Derived Ammonium Salts for Long-Acting and Sensory-Selective Nerve Blockades","authors":"Yu Deng,Bingbing Xiang,Han Yang,Xudong Luo,Chaoyi Deng,Wensheng Zhang","doi":"10.1021/acs.jmedchem.6c01940","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01940","url":null,"abstract":"Local anesthetics (LAs), a type of substance with the ability of blocking nerve fiber conduction, are indispensable in clinical practice for pain relief. However, the duration of action and sensory-motor nerve selectivity of conventional LAs require further optimization. Herein, we wish to report the discovery of novel ammonium salts derived from natural cinchona alkaloids for long-acting and sensory-selective nerve blockades. The bicyclic quincoridine skeleton exhibited superior nerve blockade efficacy compared to acyclic and monocyclic analogs. Compound CLA-1-3 produced prolonged nerve blockade (over 50 h) in the rat sciatic nerve block model, possessing an IC50 value of approximately 0.39 μmol/L for voltage-gated sodium channel inhibition. On the other hand, at a concentration range of 0.30% to 0.60%, compound CLA-3-5 achieved sensory-selective nerve blockade lasting up to 3 h. The candidate molecules and underlying mechanistic insights will be valuable assets for drug development and therapeutic innovation.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"11 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152134","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 : 2026-10-12DOI: 10.1021/acs.jmedchem.6c02004
Simona Barone,Abraham Eafa,Ivana Bello,Gessica Filocamo,Alessia Alberico,Emilia Cassese,Anna Guadagni,Heiko Rebmann,Emanuela Cosentino,Juana Goulart Stollmaier,Aubry K. Miller,Vincenzo Summa,Longlong Wang,Elisabetta Panza,David W. Christianson,Margherita Brindisi
We herein describe the structure-based design, synthesis and biological evaluation of a new class of histone deacetylase 6 (HDAC6) inhibitors guided by X-ray crystal structures of our previously identified compounds 13-15. X-ray co-crystal structures of second-generation inhibitors 19b (Subseries I) and 20b (Subseries II) within zHDAC6 CD2 confirmed that these compounds behave as highly potent HDAC6 inhibitors with the ability to engage the S531 residue in the L2 loop HDAC6 catalytic domain. Western-blot analysis confirmed the target engagement in cell-based settings, through the increase of acetylated tubulin levels, without significant variation in the histone acetylation status. Compound 20b extensively reduced the viability of A549 cells in both 2- and 3-dimensional cell cultures, through the activation of pro-autophagic pathways. In addition, HDAC6 inhibition impaired the nucleation of stress-granules, confirming the ability of these compounds to modulate liquid−liquid phase separation, an emerging HDAC6-driven hallmark in cancer.
{"title":"Structure-Based Design of HDAC6 Inhibitors Targeting the L2 Pocket: Modulating Autophagy and Liquid−Liquid Phase Separation in Lung Cancer","authors":"Simona Barone,Abraham Eafa,Ivana Bello,Gessica Filocamo,Alessia Alberico,Emilia Cassese,Anna Guadagni,Heiko Rebmann,Emanuela Cosentino,Juana Goulart Stollmaier,Aubry K. Miller,Vincenzo Summa,Longlong Wang,Elisabetta Panza,David W. Christianson,Margherita Brindisi","doi":"10.1021/acs.jmedchem.6c02004","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02004","url":null,"abstract":"We herein describe the structure-based design, synthesis and biological evaluation of a new class of histone deacetylase 6 (HDAC6) inhibitors guided by X-ray crystal structures of our previously identified compounds 13-15. X-ray co-crystal structures of second-generation inhibitors 19b (Subseries I) and 20b (Subseries II) within zHDAC6 CD2 confirmed that these compounds behave as highly potent HDAC6 inhibitors with the ability to engage the S531 residue in the L2 loop HDAC6 catalytic domain. Western-blot analysis confirmed the target engagement in cell-based settings, through the increase of acetylated tubulin levels, without significant variation in the histone acetylation status. Compound 20b extensively reduced the viability of A549 cells in both 2- and 3-dimensional cell cultures, through the activation of pro-autophagic pathways. In addition, HDAC6 inhibition impaired the nucleation of stress-granules, confirming the ability of these compounds to modulate liquid−liquid phase separation, an emerging HDAC6-driven hallmark in cancer.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"44 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152142","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 : 2026-10-12DOI: 10.1021/acs.jmedchem.6c01845
Li Chen,Yutong Wang,Jun Yang,Qian Li,Shuming Chen,Yong Wang,Wuyu Mao,Jifa Zhang
Specifically disrupting lipid droplets (LDs) is an effective strategy for ablating tumor cells through photodynamic therapy (PDT). However, most reported LD probes possess short excitation/emission wavelengths, limiting tissue penetration, and LD-targeted theranostic probes remain underdeveloped. In this work, we first developed a family of near-infrared (NIR) charge-neutral and lipid droplet-targeting cyanine photosensitizers by systematically introducing heavy atoms (Br/I) at different sites of electrically neutral BF2-bridged cyanine (BCy5). These BCy photosensitizers retain the characteristic near-infrared absorption (>650 nm) and high molar extinction coefficients of classical cyanine dyes while exhibiting good singlet oxygen quantum yields. Notably, BCy5-Br1−BCy5-Br3 nanoparticles with high LD specificity exhibit significant PDT efficacy at submicromolar concentrations and, by inducing oxidative stress and lipid peroxidation (LPO) accumulation, concurrently trigger apoptosis and ferroptosis, effectively suppressing melanoma growth in vivo. This work provides vital insights into design principles and transformation of LD-targeting NIR cyanine photosensitizers for cancer PDT.
{"title":"Rational Design of Near-Infrared Difluoroboron Cyanine Photosensitizers for Lipid Droplet-Targeting Imaging and Tumor Therapy","authors":"Li Chen,Yutong Wang,Jun Yang,Qian Li,Shuming Chen,Yong Wang,Wuyu Mao,Jifa Zhang","doi":"10.1021/acs.jmedchem.6c01845","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01845","url":null,"abstract":"Specifically disrupting lipid droplets (LDs) is an effective strategy for ablating tumor cells through photodynamic therapy (PDT). However, most reported LD probes possess short excitation/emission wavelengths, limiting tissue penetration, and LD-targeted theranostic probes remain underdeveloped. In this work, we first developed a family of near-infrared (NIR) charge-neutral and lipid droplet-targeting cyanine photosensitizers by systematically introducing heavy atoms (Br/I) at different sites of electrically neutral BF2-bridged cyanine (BCy5). These BCy photosensitizers retain the characteristic near-infrared absorption (>650 nm) and high molar extinction coefficients of classical cyanine dyes while exhibiting good singlet oxygen quantum yields. Notably, BCy5-Br1−BCy5-Br3 nanoparticles with high LD specificity exhibit significant PDT efficacy at submicromolar concentrations and, by inducing oxidative stress and lipid peroxidation (LPO) accumulation, concurrently trigger apoptosis and ferroptosis, effectively suppressing melanoma growth in vivo. This work provides vital insights into design principles and transformation of LD-targeting NIR cyanine photosensitizers for cancer PDT.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"10 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152135","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}
Chronic hepatitis C virus (HCV) infection remains a critical global public health burden affecting hundreds of millions of people worldwide. The emergence of antiviral resistance persistently undermines the long-term clinical efficacy of current direct-acting antiviral (DAA) regimens, creating an urgent need for therapeutics with different mechanisms of action. Host-directed multi-target therapy offers a promising avenue to overcome DAA resistance, yet dual inhibitors targeting HCV-essential host kinase phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ) and epigenetic regulator histone deacetylases (HDACs) have not been reported for HCV treatment to date. Herein, we describe the rational design, chemical synthesis, and comprehensive biological evaluation of a series of novel thiazolamide-based dual PI4KIIIβ/HDAC inhibitors. Lead compounds displayed potent dual-target enzymatic inhibition, robust in vitro anti-HCV activity and excellent in vivo tolerability. This work establishes a novel host-directed dual-target therapeutic paradigm for HCV, providing a viable strategy to address the unmet clinical challenge of DAA resistance.
{"title":"Discovery of Thiazolamide-based PI4KIIIβ/HDAC Dual Inhibitors with Potent Activity against Hepatitis C Virus","authors":"Enyuan Wang,Yi Xue,Shuolei Jia,Shichao Chen,Yanhong Gao,Qinglan Hu,Fang Han,Xiuqin Ruan,Ming Chen,Min Guo,Qingfa Zhou","doi":"10.1021/acs.jmedchem.6c01344","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01344","url":null,"abstract":"Chronic hepatitis C virus (HCV) infection remains a critical global public health burden affecting hundreds of millions of people worldwide. The emergence of antiviral resistance persistently undermines the long-term clinical efficacy of current direct-acting antiviral (DAA) regimens, creating an urgent need for therapeutics with different mechanisms of action. Host-directed multi-target therapy offers a promising avenue to overcome DAA resistance, yet dual inhibitors targeting HCV-essential host kinase phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ) and epigenetic regulator histone deacetylases (HDACs) have not been reported for HCV treatment to date. Herein, we describe the rational design, chemical synthesis, and comprehensive biological evaluation of a series of novel thiazolamide-based dual PI4KIIIβ/HDAC inhibitors. Lead compounds displayed potent dual-target enzymatic inhibition, robust in vitro anti-HCV activity and excellent in vivo tolerability. This work establishes a novel host-directed dual-target therapeutic paradigm for HCV, providing a viable strategy to address the unmet clinical challenge of DAA resistance.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"53 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152139","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}
Transcription factor EB (TFEB) is a promising target for autophagy regulation and cancer therapy, yet it has long been regarded as an undruggable protein. Starting from eltrombopag, an FDA-approved agent that exhibits both thrombopoietin receptor (Tpo-R) agonistic activity and TFEB inhibitory potency, we performed systematic structure−activity relationship optimization and identified DCL1191 as a potent, selective, and orally bioavailable TFEB inhibitor. DCL1191 binds TFEB with a Kd of 80.5 nM and disrupts the TFEB-DNA interaction with an IC50 of 60.5 nM. Computational modeling combined with site-directed mutagenesis elucidated its precise binding mode. DCL1191 exhibits diminished activity toward Tpo-R and MITF. Mechanistically, DCL1191 effectively represses the transcription of TFEB target genes and blocks intracellular autophagic flux. In autophagy-hyperactivated U87 glioblastoma cells, DCL1191 substantially sensitizes tumor cells to temozolomide chemotherapy. Pharmacokinetic evaluation in rats further demonstrated that DCL1191 possesses an i.v. half-life of 16.33 h and satisfactory oral bioavailability of 18.77%.
{"title":"Development of DCL1191 as a Potent, Selective and Orally Bioavailable Inhibitor for Autophagy-Associated Transcription Factor EB (TFEB)","authors":"Changle Du,Yaping Rong,Zilu Wang,Tongtong Wang,Yuqi Lin,Yuhan Luo,Yuhan Su,Pengfei Fang,Biao Yu,Zhen Wang,Jing Wang,Ke Ding","doi":"10.1021/acs.jmedchem.6c01755","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01755","url":null,"abstract":"Transcription factor EB (TFEB) is a promising target for autophagy regulation and cancer therapy, yet it has long been regarded as an undruggable protein. Starting from eltrombopag, an FDA-approved agent that exhibits both thrombopoietin receptor (Tpo-R) agonistic activity and TFEB inhibitory potency, we performed systematic structure−activity relationship optimization and identified DCL1191 as a potent, selective, and orally bioavailable TFEB inhibitor. DCL1191 binds TFEB with a Kd of 80.5 nM and disrupts the TFEB-DNA interaction with an IC50 of 60.5 nM. Computational modeling combined with site-directed mutagenesis elucidated its precise binding mode. DCL1191 exhibits diminished activity toward Tpo-R and MITF. Mechanistically, DCL1191 effectively represses the transcription of TFEB target genes and blocks intracellular autophagic flux. In autophagy-hyperactivated U87 glioblastoma cells, DCL1191 substantially sensitizes tumor cells to temozolomide chemotherapy. Pharmacokinetic evaluation in rats further demonstrated that DCL1191 possesses an i.v. half-life of 16.33 h and satisfactory oral bioavailability of 18.77%.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"9 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152136","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 : 2026-10-10DOI: 10.1021/acs.jmedchem.6c02664
Lingzhou Zhao,Liyan Bai,Jiamin Zhu,Li Sun,Xinyu Liu,Xin Lu,Jianping Zhang,Xiaoping Xu,Shaoli Song
Abstract The HER2-targeted nanobody NB46 was evaluated for labeling strategy flexibility and thermostability. Random and site-specific 68Ga labeling strategies were compared. Both conjugates exhibited high HER2 affinity, comparable to unmodified NB46. Cellular uptake, pharmacokinetics, micro-PET/CT imaging, and biodistribution in HER2-positive and HER2-negative tumor-bearing mice revealed no significant differences between the two strategies. NB46 retained HER2 affinity at temperatures up to 90 °C, demonstrating exceptional thermostability. Both conjugates achieved >95% radiochemical yields at all tested temperatures. Micro-PET/CT imaging showed sustained high tumor uptake with renal clearance as the primary elimination pathway. Blocking studies confirmed that NB46 and trastuzumab competitively bind to HER2. Elevated labeling temperatures did not compromise tumor targeting but resulted in a mild increase in renal uptake, notably for the random conjugate at 90 °C. These findings suggest that random labeling may represent a simpler, equally effective alternative for 68Ga-NB46 preparation, and confirm the excellent thermostability of this nanobody scaffold.
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