Sirtuin 2 (SIRT2) is a nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacylase implicated in cancer and neurodegeneration. Here, we report acyl-lysine peptide inhibitors bearing methyl-branched or cyclopropyl-modified acyl chains with low-nanomolar inhibitory potency. Their prolonged residence time and minimal catalytic turnover, confirmed by kinetic analysis, support a “slow substrate” inhibition mechanism. Ternary crystal structures of SIRT2−peptide−NAD+ complexes are consistent with a rate-limiting initial nucleophilic attack of the amide oxygen on NAD+. The inhibitors stabilize a catalytically competent yet unproductive enzyme state, distinct from thiocarbonyl inhibitors that form stalled intermediates with NAD+. Comparative structural and biochemical analyses with SIRT1 and SIRT3 reveal isoform-specific acyl chain trajectories underlying selectivity. Extension to potentially naturally occurring or drug-derived Nε-lysine modifications, i.e., phytanoyl- and ibuprofenyl-lysine, demonstrates that diverse branched acyl groups inhibit SIRT2. In cells, optimized inhibitors show low-nanomolar target engagement and induce robust α-tubulin hyperacetylation, establishing slow substrate inhibition as a strategy for selective sirtuin targeting.
{"title":"Alkyl-Branched Acyl-Lysine Peptides as Potent Cell-Permeable Slow-Substrate Inhibitors of SIRT2","authors":"Florian Friedrich,Marat Meleshin,Diana Kalbas,Franziska Kollmer,Niklas Papenkordt,Armin Mauerer,Jan Ruprecht,Sebastian Hilscher,Matthes Zessin,Cordelia Schiene-Fischer,Lin Zhang,Laura Graf,Wolfgang Sippl,Oliver Einsle,Manfred Jung,Mike Schutkowski","doi":"10.1021/acs.jmedchem.6c01275","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01275","url":null,"abstract":"Sirtuin 2 (SIRT2) is a nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacylase implicated in cancer and neurodegeneration. Here, we report acyl-lysine peptide inhibitors bearing methyl-branched or cyclopropyl-modified acyl chains with low-nanomolar inhibitory potency. Their prolonged residence time and minimal catalytic turnover, confirmed by kinetic analysis, support a “slow substrate” inhibition mechanism. Ternary crystal structures of SIRT2−peptide−NAD+ complexes are consistent with a rate-limiting initial nucleophilic attack of the amide oxygen on NAD+. The inhibitors stabilize a catalytically competent yet unproductive enzyme state, distinct from thiocarbonyl inhibitors that form stalled intermediates with NAD+. Comparative structural and biochemical analyses with SIRT1 and SIRT3 reveal isoform-specific acyl chain trajectories underlying selectivity. Extension to potentially naturally occurring or drug-derived Nε-lysine modifications, i.e., phytanoyl- and ibuprofenyl-lysine, demonstrates that diverse branched acyl groups inhibit SIRT2. In cells, optimized inhibitors show low-nanomolar target engagement and induce robust α-tubulin hyperacetylation, establishing slow substrate inhibition as a strategy for selective sirtuin targeting.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"1 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221745","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 : 2026-10-20DOI: 10.1021/acs.jmedchem.5c02647
Roberta Mazzucato,Nicoló Iotti,Eleonora Ghidini,Andrea Rizzi,Fabio Rancati,Serena Bertolini,Fabio Bignami,Alessandro Fioni,Valentina Mileo,Fabio Vaccaro,Allisson Freire Bento,Annalisa Murgo,Anna Maria Capelli,Benjamin Paul Whittaker,Charlotte Matthews,Elizabeth Hann,Daniel Todd,Veronica Marinoni,Laura Carzaniga
Preclinical studies highlighted the key role of Discoidin Domain Receptors (DDRs) in fibrotic processes, making them promising targets for Idiopathic Pulmonary Fibrosis (IPF) treatment. In this work, we describe the design of a novel class of DDR inhibitors and their subsequent optimization toward inhaled delivery. Following a structure-based approach, we identified two chemical series based on 5:6 heterocyclic cores showing nanomolar affinity for DDR1 and DDR2 and a promising kinome selectivity profile. An inhaled-by-design medchem strategy was then applied to optimize potency, phys-chem, and in vitro ADME properties, tailored to achieve lung-restricted compounds. This effort resulted in the discovery of compound 25, a novel and highly potent DDR inhibitor that combined antifibrotic activity in a TGFβ-induced in vitro fibrosis model with an outstanding pharmacokinetic profile and the desired lung-targeted behavior following inhaled administration.
{"title":"Lung-Tailored Pyrrolo-pyrimidine DDR Inhibitors Designed for Optimized Local Delivery","authors":"Roberta Mazzucato,Nicoló Iotti,Eleonora Ghidini,Andrea Rizzi,Fabio Rancati,Serena Bertolini,Fabio Bignami,Alessandro Fioni,Valentina Mileo,Fabio Vaccaro,Allisson Freire Bento,Annalisa Murgo,Anna Maria Capelli,Benjamin Paul Whittaker,Charlotte Matthews,Elizabeth Hann,Daniel Todd,Veronica Marinoni,Laura Carzaniga","doi":"10.1021/acs.jmedchem.5c02647","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02647","url":null,"abstract":"Preclinical studies highlighted the key role of Discoidin Domain Receptors (DDRs) in fibrotic processes, making them promising targets for Idiopathic Pulmonary Fibrosis (IPF) treatment. In this work, we describe the design of a novel class of DDR inhibitors and their subsequent optimization toward inhaled delivery. Following a structure-based approach, we identified two chemical series based on 5:6 heterocyclic cores showing nanomolar affinity for DDR1 and DDR2 and a promising kinome selectivity profile. An inhaled-by-design medchem strategy was then applied to optimize potency, phys-chem, and in vitro ADME properties, tailored to achieve lung-restricted compounds. This effort resulted in the discovery of compound 25, a novel and highly potent DDR inhibitor that combined antifibrotic activity in a TGFβ-induced in vitro fibrosis model with an outstanding pharmacokinetic profile and the desired lung-targeted behavior following inhaled administration.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"22 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221747","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}
Heart failure (HF) remains a severe global cardiovascular disease with limited targeted therapies. Mitochondrial deacetylase SIRT3 is a promising therapeutic target for HF, yet current SIRT3 agonists suffer from low potency and poor isoform selectivity. Herein, we adopted a modular biomimetic strategy to synthesize a series of macrocyclic sulfonamides and systematically explored their structure-activity relationships. The lead compound 2b (Y0855) exhibited potent SIRT3 agonistic activity (EC50 = 12.6 μM, and Emax = 4.05) and excellent selectivity over SIRT1/2/6. Mechanistically, 2b alleviated cardiomyocyte oxidative stress, cell injury and fibrosis via SIRT3 activation. In a doxorubicin-induced HF mouse model, it markedly restored cardiac function and mitigated myocardial damage. Moreover, 2b possessed improved metabolic stability, making it a valuable lead compound for anti-HF drug development targeting SIRT3.
{"title":"Modular Biomimetic Strategy toward Discovery of Macrocyclic Sulfonamides as SIRT3 Activators against Heart Failure","authors":"Xiaoxiao Yang,Simin Liu,Yunxia Cui,Hepeng Liu,Xiaolong Ma,Zhongliang Xu,Tongyu Bi,Xiaojun Xu,Jian Zhang,Weibo Yang","doi":"10.1021/acs.jmedchem.6c01960","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01960","url":null,"abstract":"Heart failure (HF) remains a severe global cardiovascular disease with limited targeted therapies. Mitochondrial deacetylase SIRT3 is a promising therapeutic target for HF, yet current SIRT3 agonists suffer from low potency and poor isoform selectivity. Herein, we adopted a modular biomimetic strategy to synthesize a series of macrocyclic sulfonamides and systematically explored their structure-activity relationships. The lead compound 2b (Y0855) exhibited potent SIRT3 agonistic activity (EC50 = 12.6 μM, and Emax = 4.05) and excellent selectivity over SIRT1/2/6. Mechanistically, 2b alleviated cardiomyocyte oxidative stress, cell injury and fibrosis via SIRT3 activation. In a doxorubicin-induced HF mouse model, it markedly restored cardiac function and mitigated myocardial damage. Moreover, 2b possessed improved metabolic stability, making it a valuable lead compound for anti-HF drug development targeting SIRT3.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"2 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221743","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}
Psoriasis is a chronic, immune-mediated inflammatory dermatosis featured by aberrant keratinocyte hyperproliferation and persistent cutaneous inflammatory infiltration, lacking curative small-molecule therapeutics. Dysregulated Janus kinase signal transducer and activator of transcription pathway (JAK/STAT) and histone deacetylase (HDAC)-dependent epigenetic signaling represented essential pathogenic axes driving psoriasis progression. Inspired by synergistic crosstalk between these two pathways and our previous work identifying anti-psoriatic JAK/HDAC dual inhibitors, a series of novel dual JAK/HDAC inhibitors were rationally designed and synthesized. Systematic enzymatic profiling revealed compound 11e exerted potent and balanced JAK2 and HDAC6 inhibitory activity (JAK2 IC50 = 2.1 nM, HDAC6 IC50 = 3.1 nM). Critically, topical cream formulation and oral administration of 11e dramatically alleviated erythema, scaling, and epidermal hyperplasia in the imiquimod-induced psoriasis mouse model. Collectively, compound 11e served as a promising lead compound for anti-psoriasis drug development, providing validated structural scaffolds for further optimization of next-generation JAK/HDAC dual inhibitors.
{"title":"Design, Synthesis, and Biological Evaluation of Janus Kinase (JAK) and Histone Deacetylase (HDAC) Dual Inhibitors for the Treatment of Psoriasis","authors":"Ruilin Liu,Yinyan Xiao,Mingyue Xue,Qian Liu,Weijie Hu,Jing Shen,Mingyang Hou,Chunquan Sheng,Yahui Huang","doi":"10.1021/acs.jmedchem.6c02310","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02310","url":null,"abstract":"Psoriasis is a chronic, immune-mediated inflammatory dermatosis featured by aberrant keratinocyte hyperproliferation and persistent cutaneous inflammatory infiltration, lacking curative small-molecule therapeutics. Dysregulated Janus kinase signal transducer and activator of transcription pathway (JAK/STAT) and histone deacetylase (HDAC)-dependent epigenetic signaling represented essential pathogenic axes driving psoriasis progression. Inspired by synergistic crosstalk between these two pathways and our previous work identifying anti-psoriatic JAK/HDAC dual inhibitors, a series of novel dual JAK/HDAC inhibitors were rationally designed and synthesized. Systematic enzymatic profiling revealed compound 11e exerted potent and balanced JAK2 and HDAC6 inhibitory activity (JAK2 IC50 = 2.1 nM, HDAC6 IC50 = 3.1 nM). Critically, topical cream formulation and oral administration of 11e dramatically alleviated erythema, scaling, and epidermal hyperplasia in the imiquimod-induced psoriasis mouse model. Collectively, compound 11e served as a promising lead compound for anti-psoriasis drug development, providing validated structural scaffolds for further optimization of next-generation JAK/HDAC dual inhibitors.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"12 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221744","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}
Threonine tyrosine kinase (TTK), a core component of the spindle assembly checkpoint, plays an essential role in mitosis, and its inhibition has emerged as a promising therapeutic strategy for human cancers. We previously reported multiple approaches to target TTK, including reversible inhibitors, covalent inhibitors, and PROTAC degraders. In this study, we advance these efforts by developing a novel monovalent degrader of TTK. The representative compound, 26, generated by appending an electrophilic monomethyl fumarate handle to a TTK inhibitor, effectively induced TTK degradation and demonstrated superior antiproliferative activity across diverse cancer cell lines. Mechanistic investigations suggested that compound 26 primarily engages RNF126 and stabilizes its association with TTK, thereby inducing TTK ubiquitination and subsequent proteasomal degradation. Collectively, this work provides the first example of a TTK molecular glue-like degrader and introduces a new electrophilic handle for the rational design of degraders with reduced nonspecific cytotoxicity.
{"title":"Discovery of Threonine Tyrosine Kinase (TTK) Degraders Utilizing an Electrophilic Monomethyl Fumarate Handle","authors":"Jian Zou,Yaoliang Sun,Beini Wen,Zihan Shi,Miao Sun,Yixuan Wang,Xinbo Wang,Lijie Lin,Shaofeng Zhang,Shuyao Zhang,He Huang,Zhang Zhang,Shilin Xu","doi":"10.1021/acs.jmedchem.6c01706","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01706","url":null,"abstract":"Threonine tyrosine kinase (TTK), a core component of the spindle assembly checkpoint, plays an essential role in mitosis, and its inhibition has emerged as a promising therapeutic strategy for human cancers. We previously reported multiple approaches to target TTK, including reversible inhibitors, covalent inhibitors, and PROTAC degraders. In this study, we advance these efforts by developing a novel monovalent degrader of TTK. The representative compound, 26, generated by appending an electrophilic monomethyl fumarate handle to a TTK inhibitor, effectively induced TTK degradation and demonstrated superior antiproliferative activity across diverse cancer cell lines. Mechanistic investigations suggested that compound 26 primarily engages RNF126 and stabilizes its association with TTK, thereby inducing TTK ubiquitination and subsequent proteasomal degradation. Collectively, this work provides the first example of a TTK molecular glue-like degrader and introduces a new electrophilic handle for the rational design of degraders with reduced nonspecific cytotoxicity.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"37 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221751","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}
Idiopathic pulmonary fibrosis (IPF) remains a progressive and fatal lung disease with a substantial unmet need for safe and effective therapies. Highly selective inhibition of phosphodiesterase 4B (PDE4B) represents a promising therapeutic strategy for IPF while avoiding nausea and vomiting associated with PDE4D inhibition. However, achieving pronounced subtype selectivity remains particularly challenging; notably, the only approved PDE4B-preferential inhibitor, nerandomilast, exhibits only approximately 9-fold selectivity for PDE4B over PDE4D. Herein, we report the identification of YKS-34, a potent PDE4B inhibitor (IC50 = 1.71 nM) exhibiting >1000-fold selectivity over PDE4A, PDE4C, and PDE4D. YKS-34 effectively suppressed TGF-β-induced fibroblast activation and LPS-induced TNF-α release in vitro. In vivo, YKS-34 showed favorable pharmacokinetic properties, lung tissue accumulation, and reduced emetic potential at tested conditions while dose-dependently improving pulmonary dysfunction and fibrotic remodeling in a bleomycin-induced IPF mouse model. Consequently, YKS-34 emerges as a highly promising, next-generation candidate for the treatment of IPF.
{"title":"Discovery of YKS-34, a Highly Selective PDE4B Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis","authors":"Tongfei Jing,Chang Fu,Runzhi Zhang,Zhuo Shi,Zhiyi Wu,Ruibo Lin,Weibin Zeng,Peiyu Zhang,Shiyang Shen,Zhenghui Kang,Yushe Yang","doi":"10.1021/acs.jmedchem.6c02578","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02578","url":null,"abstract":"Idiopathic pulmonary fibrosis (IPF) remains a progressive and fatal lung disease with a substantial unmet need for safe and effective therapies. Highly selective inhibition of phosphodiesterase 4B (PDE4B) represents a promising therapeutic strategy for IPF while avoiding nausea and vomiting associated with PDE4D inhibition. However, achieving pronounced subtype selectivity remains particularly challenging; notably, the only approved PDE4B-preferential inhibitor, nerandomilast, exhibits only approximately 9-fold selectivity for PDE4B over PDE4D. Herein, we report the identification of YKS-34, a potent PDE4B inhibitor (IC50 = 1.71 nM) exhibiting >1000-fold selectivity over PDE4A, PDE4C, and PDE4D. YKS-34 effectively suppressed TGF-β-induced fibroblast activation and LPS-induced TNF-α release in vitro. In vivo, YKS-34 showed favorable pharmacokinetic properties, lung tissue accumulation, and reduced emetic potential at tested conditions while dose-dependently improving pulmonary dysfunction and fibrotic remodeling in a bleomycin-induced IPF mouse model. Consequently, YKS-34 emerges as a highly promising, next-generation candidate for the treatment of IPF.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"13 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221760","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}
UBE2 family of E2 ubiquitin-conjugating enzymes occupy central positions in multiple ubiquitination pathways and have been implicated in cancers, motivating efforts to develop chemical probes to interrogate their functions. In this study, we identified XY54 as a covalent modifier of UBE2D2 that engages both C85 and C111 by using an electrophile-first screening approach coupled with X-ray crystallography. Structure-guided structure−activity relationship optimization of XY54 yielded XY54-24, in which modifications of the amide and ester groups of XY54 selectively abolished its binding to C111 while enhancing affinity for C85. XY54-24 inhibited UBE2D2 enzymatic activity in vitro and suppressed the proliferation of A549 lung cancer cells. Collectively, this study identifies covalent aminothiazole scaffold inhibitors for targeting UBE2D2 and provides a structural foundation for further development of selective UBE2D2 chemical probes.
{"title":"Electrophile-First Screening Identifies Covalent Aminothiazole Scaffold Inhibitors for Ubiquitin-Conjugating Enzyme UBE2D2","authors":"Siying Liu,Tao Zheng,Xinyu Wu,Huiling Wang,Shuaishuai Ni,Yilin Dou,Boyi Li,Lu Wang,Yunyuan Huang,Xin Chen,Jinrong Min","doi":"10.1021/acs.jmedchem.6c01896","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01896","url":null,"abstract":"UBE2 family of E2 ubiquitin-conjugating enzymes occupy central positions in multiple ubiquitination pathways and have been implicated in cancers, motivating efforts to develop chemical probes to interrogate their functions. In this study, we identified XY54 as a covalent modifier of UBE2D2 that engages both C85 and C111 by using an electrophile-first screening approach coupled with X-ray crystallography. Structure-guided structure−activity relationship optimization of XY54 yielded XY54-24, in which modifications of the amide and ester groups of XY54 selectively abolished its binding to C111 while enhancing affinity for C85. XY54-24 inhibited UBE2D2 enzymatic activity in vitro and suppressed the proliferation of A549 lung cancer cells. Collectively, this study identifies covalent aminothiazole scaffold inhibitors for targeting UBE2D2 and provides a structural foundation for further development of selective UBE2D2 chemical probes.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"1 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221697","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}
CDK9 has emerged as a promising therapeutic target for anticancer drug development. Although multiple CDK9 inhibitors have entered clinical evaluation, differentiated scaffolds with convincing activity and tolerability in solid tumors remain limited. In this study, we identified a series of indole-based CDK9 inhibitors through virtual screening and structure-based drug design, and systematically evaluated their therapeutic potential in hepatocellular carcinoma (HCC). Among these compounds, W24 exhibited potent CDK9 inhibitory activity (IC50 = 0.9 nM) and a preliminary kinase selectivity profile. W24 effectively induced HCC cell death in vitro, which was accompanied by DNA damage and downregulation of the anti-apoptotic protein Mcl-1. Furthermore, W24 significantly suppressed tumor growth in HepG2 and Huh-7 xenograft models with an acceptable safety profile under the tested dosing regimen. Collectively, these findings highlight W24 as a promising lead compound and provide valuable insights for the development of next-generation CDK9 inhibitors for the treatment of hepatocellular carcinoma.
{"title":"Discovery and Optimization of Indole-Based CDK9 Inhibitors for Hepatocellular Carcinoma","authors":"Tizhi Wu,Wenyi Zhou,Feihai Ma,Zexu Wang,Jingyi Ding,Jing Liu,Yifang Liu,Shiqi Wu,Zhixia Qiu,Kaibo Wang,Zhiyu Li,Hongxi Wu,Jinlei Bian","doi":"10.1021/acs.jmedchem.6c01374","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01374","url":null,"abstract":"CDK9 has emerged as a promising therapeutic target for anticancer drug development. Although multiple CDK9 inhibitors have entered clinical evaluation, differentiated scaffolds with convincing activity and tolerability in solid tumors remain limited. In this study, we identified a series of indole-based CDK9 inhibitors through virtual screening and structure-based drug design, and systematically evaluated their therapeutic potential in hepatocellular carcinoma (HCC). Among these compounds, W24 exhibited potent CDK9 inhibitory activity (IC50 = 0.9 nM) and a preliminary kinase selectivity profile. W24 effectively induced HCC cell death in vitro, which was accompanied by DNA damage and downregulation of the anti-apoptotic protein Mcl-1. Furthermore, W24 significantly suppressed tumor growth in HepG2 and Huh-7 xenograft models with an acceptable safety profile under the tested dosing regimen. Collectively, these findings highlight W24 as a promising lead compound and provide valuable insights for the development of next-generation CDK9 inhibitors for the treatment of hepatocellular carcinoma.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"225 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221695","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}
Boronate-based myocardial perfusion tracers represent a promising scaffold for quantitative SPECT myocardial blood flow (MBF) imaging. In this study, five fluorinated 99mTc-labeled boronate derivatives were designed to systematically investigate the influence of fluorine substitution patterns on tracer pharmacokinetics and imaging performance. The fluorination pattern markedly influenced myocardial uptake, hepatic clearance, and overall biodistribution, with 99mTc-2F-HMPBA (99mTc-2F) and 99mTc-3F-HMPBA (99mTc-3F) exhibiting the most favorable profiles. Mechanistic evaluation using isolated heart perfusion demonstrated a high first-pass extraction fraction over a wide range of coronary flow rates, while dynamic SPECT imaging in swine showed tracer-derived K1 values comparable to 13N−NH3 PET-derived MBF. In particular, 99mTc-3F exhibited a more balanced pharmacokinetic profile with improved heart-to-liver contrast. These findings establish fluorine substitution as an effective strategy for tuning the pharmacokinetic behavior of boronate-based myocardial perfusion tracers and identify 99mTc-3F as a promising lead for quantitative SPECT myocardial perfusion imaging.
{"title":"Influence of Fluorine Substitution Pattern in Arylboronic Acid Caps on the Myocardial Perfusion Imaging Properties of Technetium Monocapped Tris(dioxime) Complexes","authors":"Ding Ding,Wanjie Ren,Yufan Gu,Min Ju,Yue Zhou,Shuyang Song,Ke Wang,Zongyao Zhang,Lei Wang,Wei Fang","doi":"10.1021/acs.jmedchem.6c02123","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02123","url":null,"abstract":"Boronate-based myocardial perfusion tracers represent a promising scaffold for quantitative SPECT myocardial blood flow (MBF) imaging. In this study, five fluorinated 99mTc-labeled boronate derivatives were designed to systematically investigate the influence of fluorine substitution patterns on tracer pharmacokinetics and imaging performance. The fluorination pattern markedly influenced myocardial uptake, hepatic clearance, and overall biodistribution, with 99mTc-2F-HMPBA (99mTc-2F) and 99mTc-3F-HMPBA (99mTc-3F) exhibiting the most favorable profiles. Mechanistic evaluation using isolated heart perfusion demonstrated a high first-pass extraction fraction over a wide range of coronary flow rates, while dynamic SPECT imaging in swine showed tracer-derived K1 values comparable to 13N−NH3 PET-derived MBF. In particular, 99mTc-3F exhibited a more balanced pharmacokinetic profile with improved heart-to-liver contrast. These findings establish fluorine substitution as an effective strategy for tuning the pharmacokinetic behavior of boronate-based myocardial perfusion tracers and identify 99mTc-3F as a promising lead for quantitative SPECT myocardial perfusion imaging.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"56 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221748","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 : 2026-10-20DOI: 10.1021/acs.jmedchem.6c01456
Junjie Chen,Weixu Wang,Xijin Qi,Naziyila Shayilan,Weiyi Zhang,Cheng Ma
The dual inhibition of phosphatidylinositol 3-kinase (PI3K) and histone deacetylase 8 (HDAC8) has emerged as a promising strategy for cervical cancer (CC) therapy. We synthesized 34 novel benzimidazole derivatives and evaluated their anti-CC cell line proliferation. The compound 50 exhibited equivalent antiproliferative effect to cisplatin (Pt) in CC cell lines SiHa, Ca Ski, and HeLa, especially in HeLa cells with an IC50 value at 1.42 ± 0.50 μM (Pt 1.70 ± 0.28 μM). Further assessment in the HeLa cell xenograft mouse model, the intraperitoneal medium- (30 mg/kg) and high-dose group (60 mg/kg) and and intragastric high-dose group (100 mg/kg) exhibited antitumor efficacy no less than that of Pt (i.p. 5 mg/kg) but much more safe during the experiment period. Mechanism studies demonstrated that 50 could inhibit the PI3K/Akt pathway and HDAC8 expression and function. These findings prove that the PI3K/HDAC8 dual inhibition may be an efficient way in cervical cancer treatment and compound 50 deserved for further development.
{"title":"Design, Synthesis, and Biological Evaluation of Novel Benzimidazole Derivatives as Dual PI3K/HDAC8 Inhibitors with Potent Anti-Cervical Cancer Activity InVivo","authors":"Junjie Chen,Weixu Wang,Xijin Qi,Naziyila Shayilan,Weiyi Zhang,Cheng Ma","doi":"10.1021/acs.jmedchem.6c01456","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01456","url":null,"abstract":"The dual inhibition of phosphatidylinositol 3-kinase (PI3K) and histone deacetylase 8 (HDAC8) has emerged as a promising strategy for cervical cancer (CC) therapy. We synthesized 34 novel benzimidazole derivatives and evaluated their anti-CC cell line proliferation. The compound 50 exhibited equivalent antiproliferative effect to cisplatin (Pt) in CC cell lines SiHa, Ca Ski, and HeLa, especially in HeLa cells with an IC50 value at 1.42 ± 0.50 μM (Pt 1.70 ± 0.28 μM). Further assessment in the HeLa cell xenograft mouse model, the intraperitoneal medium- (30 mg/kg) and high-dose group (60 mg/kg) and and intragastric high-dose group (100 mg/kg) exhibited antitumor efficacy no less than that of Pt (i.p. 5 mg/kg) but much more safe during the experiment period. Mechanism studies demonstrated that 50 could inhibit the PI3K/Akt pathway and HDAC8 expression and function. These findings prove that the PI3K/HDAC8 dual inhibition may be an efficient way in cervical cancer treatment and compound 50 deserved for further development.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"11 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221750","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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