PIK3CA, which encodes the p110α catalytic subunit of PI3Kα, is frequently mutated in a variety of cancers. Consequently, targeting PI3Kα using a small-molecule inhibitor represents a key therapeutic strategy for treating cancers driven by PIK3CA mutations. In recent years, several selective PI3Kα inhibitors have entered clinical investigations. In this study, to obtain an ideal PI3Kα inhibitor with high selectivity, we compared the amino acid residues within the ATP-binding pockets of four class I PI3K isoforms (α, β, γ, and δ) and observed notable differences in residues around hinge regions. Based on this, we designed and synthesized a series of novel disubstituted l-prolinamide derivatives. Biological evaluation showed that compound 26 exhibited high PI3Kα selectivity over PI3Kβ (1268-fold), PI3Kγ (350-fold), and PI3Kδ (206-fold). Further assessment of its pharmacokinetic properties and in vivo efficacy underscored the promising preclinical potential of compound 26.
{"title":"Discovery of Novel Disubstituted l-Prolinamide Derivatives as Selective PI3Kα Inhibitors for Anticancer Therapy.","authors":"Yunxia Wang,Qiuyan Xu,Linsheng Zhong,Yanfei Zhang,Xiancai Ye,Qingwang Liu,Qianmao Liang,Xiaoqing Lv","doi":"10.1021/acs.jmedchem.5c03376","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03376","url":null,"abstract":"PIK3CA, which encodes the p110α catalytic subunit of PI3Kα, is frequently mutated in a variety of cancers. Consequently, targeting PI3Kα using a small-molecule inhibitor represents a key therapeutic strategy for treating cancers driven by PIK3CA mutations. In recent years, several selective PI3Kα inhibitors have entered clinical investigations. In this study, to obtain an ideal PI3Kα inhibitor with high selectivity, we compared the amino acid residues within the ATP-binding pockets of four class I PI3K isoforms (α, β, γ, and δ) and observed notable differences in residues around hinge regions. Based on this, we designed and synthesized a series of novel disubstituted l-prolinamide derivatives. Biological evaluation showed that compound 26 exhibited high PI3Kα selectivity over PI3Kβ (1268-fold), PI3Kγ (350-fold), and PI3Kδ (206-fold). Further assessment of its pharmacokinetic properties and in vivo efficacy underscored the promising preclinical potential of compound 26.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"49 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147471833","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 : 2026-03-18DOI: 10.1021/acs.jmedchem.5c03226
Gyula Bencze, Prabhadevi Venkataramani, Elad Elkayam, Keith D. Rivera, Ankur Garg, Istvan Szabadakai, Laszlo Orfi, Leemor Joshua-Tor, Darryl J. Pappin, Nicholas K. Tonks
Fermented wheat germ extract (FWGE), a nutraceutical with reported anticancer properties, contains numerous biologically active molecules, but its therapeutic constituents remain unclear. In this study, we identify and characterize a novel small-molecule protein kinase inhibitor isolated from FWGE, designated F10V6W0. Through preparative high-performance liquid chromatography and structural elucidation via X-ray crystallography, this compound was revealed to be a unique benzothiazole. Kinase profiling demonstrated its selectivity toward PIM and DYRK protein kinase families. A chemically synthesized version (CSH-4044), mirrored the activity of the natural product, confirming structural integrity and biological equivalence. We determined the cocrystal structure of CSH-4044 bound to PIM1, revealing ATP-competitive binding and critical hydrophobic and hydrogen-bonding interactions. Functionally, CSH-4044 suppressed PIM3-driven BAD phosphorylation in pancreatic cancer cells and reduced DYRK1A-mediated Tau phosphorylation in neuronal cells. Our findings position CSH-4044 as a promising lead for targeting PIM and DYRK kinase families and highlight FWGE as a potential therapeutic compounds.
{"title":"Identification and Validation of an Inhibitor of the Protein Kinases PIM and DYRK","authors":"Gyula Bencze, Prabhadevi Venkataramani, Elad Elkayam, Keith D. Rivera, Ankur Garg, Istvan Szabadakai, Laszlo Orfi, Leemor Joshua-Tor, Darryl J. Pappin, Nicholas K. Tonks","doi":"10.1021/acs.jmedchem.5c03226","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03226","url":null,"abstract":"Fermented wheat germ extract (FWGE), a nutraceutical with reported anticancer properties, contains numerous biologically active molecules, but its therapeutic constituents remain unclear. In this study, we identify and characterize a novel small-molecule protein kinase inhibitor isolated from FWGE, designated F10V6W0. Through preparative high-performance liquid chromatography and structural elucidation via X-ray crystallography, this compound was revealed to be a unique benzothiazole. Kinase profiling demonstrated its selectivity toward PIM and DYRK protein kinase families. A chemically synthesized version (CSH-4044), mirrored the activity of the natural product, confirming structural integrity and biological equivalence. We determined the cocrystal structure of CSH-4044 bound to PIM1, revealing ATP-competitive binding and critical hydrophobic and hydrogen-bonding interactions. Functionally, CSH-4044 suppressed PIM3-driven BAD phosphorylation in pancreatic cancer cells and reduced DYRK1A-mediated Tau phosphorylation in neuronal cells. Our findings position CSH-4044 as a promising lead for targeting PIM and DYRK kinase families and highlight FWGE as a potential therapeutic compounds.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"24 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478740","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}
Drug-induced liver injury (DILI) in diabetes remains a critical and clinically challenging disease due to the lack of effective theranostic tools. Herein, we report SKCLS, a carboxylesterase (CE, an enzyme overexpressed in the liver)-activatable hydrogen sulfide (H2S) donor integrating near-infrared fluorescence and chemiluminescence (NIRF/CHL) imaging for DILI theranostics in diabetes. Upon CE-mediated hydrolysis, SKCLS undergoes a self-immolative reaction to generate NIRF and CHL signals for the precise tracking of liver repair processes and the release of carbonyl sulfide (COS), which can be rapidly converted to H2S via carbonic anhydrase (CA). The in situ delivery of H2S effectively alleviates oxidative injury by activating the Keap1-Nrf2/ARE pathway and accelerates hepatic functional recovery. This study successfully establishes an innovative theranostic platform that combines dual-mode diagnosis and H2S therapy. It not only effectively solves the theranostic problems associated with DILI management in diabetes but also opens up new avenues for managing other injury-related liver diseases.
{"title":"Hydrogen Sulfide Donor Featuring Dual-Modal Imaging for the Theranostic Management of Drug-Induced Liver Injury.","authors":"Yue Wang,Fang Yuan,Chenshu Wu,Lulu Ning,Yihan Zhao,Ji-Wei Shen,Tony D James,Jianjian Zhang,Yuan Guo","doi":"10.1021/acs.jmedchem.5c03427","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03427","url":null,"abstract":"Drug-induced liver injury (DILI) in diabetes remains a critical and clinically challenging disease due to the lack of effective theranostic tools. Herein, we report SKCLS, a carboxylesterase (CE, an enzyme overexpressed in the liver)-activatable hydrogen sulfide (H2S) donor integrating near-infrared fluorescence and chemiluminescence (NIRF/CHL) imaging for DILI theranostics in diabetes. Upon CE-mediated hydrolysis, SKCLS undergoes a self-immolative reaction to generate NIRF and CHL signals for the precise tracking of liver repair processes and the release of carbonyl sulfide (COS), which can be rapidly converted to H2S via carbonic anhydrase (CA). The in situ delivery of H2S effectively alleviates oxidative injury by activating the Keap1-Nrf2/ARE pathway and accelerates hepatic functional recovery. This study successfully establishes an innovative theranostic platform that combines dual-mode diagnosis and H2S therapy. It not only effectively solves the theranostic problems associated with DILI management in diabetes but also opens up new avenues for managing other injury-related liver diseases.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"88 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147471834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
DNA methyltransferase 1 (DNMT1) overexpression is associated with aberrant methylation and tumorigenesis, making its detection vital for tumor diagnosis. In this study, RG108 derivatives bearing cysteine-targeted covalent moieties were constructed as warheads for the DNMT1 detectors. Following affinity assessment by surface plasmon resonance, warheads containing a 2-fluoroacrylamido moiety were selected for preparing fluorescein-labeled probes 20a and 20b. In-gel fluorescence scanning and competitive assays confirmed that the probes can covalently bind to DNMT1 at the S-adenosyl-l-homocysteine site. Probe 20b showed concentration- and time-dependent fluorescence in HeLa cells and demonstrated detection performance comparable to DNMT1 antibody with superior nuclear membrane permeability across diverse cell lines. Notably, the relative fluorescence unit ratios of probe 20b to 4′,6-diamidino-2′-phenylindole in clinical cervical exfoliated cells showed significant differences among normal cells, low-grade squamous intraepithelial lesion cells, high-grade squamous intraepithelial lesion cells, and cancer cells, indicating its great potential as a tumor diagnostic agent.
{"title":"Development of Covalent Small-Molecule Fluorescent Probes for DNA Methyltransferase 1 Detection in Cancer Cells and Cervical Exfoliated Cells","authors":"Peijia Jin, Qunxian Cheng, Xiaoqian Hong, Qingmiao Jia, Jingyi Liu, Ling Xu, Qian Zhang","doi":"10.1021/acs.jmedchem.5c03529","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03529","url":null,"abstract":"DNA methyltransferase 1 (DNMT1) overexpression is associated with aberrant methylation and tumorigenesis, making its detection vital for tumor diagnosis. In this study, RG108 derivatives bearing cysteine-targeted covalent moieties were constructed as warheads for the DNMT1 detectors. Following affinity assessment by surface plasmon resonance, warheads containing a 2-fluoroacrylamido moiety were selected for preparing fluorescein-labeled probes <b>20a</b> and <b>20b</b>. In-gel fluorescence scanning and competitive assays confirmed that the probes can covalently bind to DNMT1 at the <i>S</i>-adenosyl-<span>l</span>-homocysteine site. Probe <b>20b</b> showed concentration- and time-dependent fluorescence in HeLa cells and demonstrated detection performance comparable to DNMT1 antibody with superior nuclear membrane permeability across diverse cell lines. Notably, the relative fluorescence unit ratios of probe <b>20b</b> to 4′,6-diamidino-2′-phenylindole in clinical cervical exfoliated cells showed significant differences among normal cells, low-grade squamous intraepithelial lesion cells, high-grade squamous intraepithelial lesion cells, and cancer cells, indicating its great potential as a tumor diagnostic agent.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"17 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478743","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 : 2026-03-17DOI: 10.1021/acs.jmedchem.6c00224
Chaofan Xu, Neeta Abraham, Nupur Bansal, Philippe N. Bolduc, Patrick Cullen, Thomas M. Carlile, Yirui Chen, Colin K. Choi, Rachelle Driscoll, Eric Stefan, Christina M. Gallo, Zhen Gao, Catherine L. Guardado, Guilherme Guimaraes, James Harvey, Sarah Huff, Dann Huh, Jessica Hurt, Melissa M. Kemp, Kwang Soo Lee, Joon Lee, Mukesh Lulla, Soumya Negi, Marta Nevalainen, Emily A. Peterson, Thomas J. Purgett, Joseph C. Santoro, Daniel R. Smith, Andreas Weihofen, Zain Yousaf, Magnus Pfaffenbach
Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by a CAG-repeat expansion in the Huntington gene (HTT). Herein, we describe the discovery of a series of HTT pre-mRNA-splicing modulators that promote the inclusion of a cryptic stop codon that in turn lowers levels of mutant Huntington protein (mHTT). Optimization of the starting thienopyridine amide core resulted in the discovery of the potent, CNS-penetrant, selective, and orally bioavailable HTT-splicing modulator BIO-6553. This lead compound is structurally distinct from existing splicing modulators, demonstrated significant HTT-lowering in both human cells and mouse YAC128 models, and has an attractive off-target profile from RASL- and RNA-seq analysis.
{"title":"Discovery and Optimization of Thienopyrazine RNA-Splicing Modulators for the Treatment of Huntington’s Disease","authors":"Chaofan Xu, Neeta Abraham, Nupur Bansal, Philippe N. Bolduc, Patrick Cullen, Thomas M. Carlile, Yirui Chen, Colin K. Choi, Rachelle Driscoll, Eric Stefan, Christina M. Gallo, Zhen Gao, Catherine L. Guardado, Guilherme Guimaraes, James Harvey, Sarah Huff, Dann Huh, Jessica Hurt, Melissa M. Kemp, Kwang Soo Lee, Joon Lee, Mukesh Lulla, Soumya Negi, Marta Nevalainen, Emily A. Peterson, Thomas J. Purgett, Joseph C. Santoro, Daniel R. Smith, Andreas Weihofen, Zain Yousaf, Magnus Pfaffenbach","doi":"10.1021/acs.jmedchem.6c00224","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c00224","url":null,"abstract":"Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by a CAG-repeat expansion in the Huntington gene (HTT). Herein, we describe the discovery of a series of HTT pre-mRNA-splicing modulators that promote the inclusion of a cryptic stop codon that in turn lowers levels of mutant Huntington protein (mHTT). Optimization of the starting thienopyridine amide core resulted in the discovery of the potent, CNS-penetrant, selective, and orally bioavailable HTT-splicing modulator BIO-6553. This lead compound is structurally distinct from existing splicing modulators, demonstrated significant HTT-lowering in both human cells and mouse YAC128 models, and has an attractive off-target profile from RASL- and RNA-seq analysis.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"87 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147466046","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 : 2026-03-17DOI: 10.1021/acs.jmedchem.5c01803
Benjamin D Horning,Cian Kingston,Gabriel M Simon,Matthew P Patricelli,David S Weinstein,Brian N Cook
Covalent modalities represent an important component of the modern medicinal chemist's toolbox for pursuing challenging targets in drug discovery. By taking a "covalent-first" approach to identifying druggable pockets on challenging-to-drug targets, we and others have expanded accessible target space and driven fragment-like hits to clinical-stage molecules. The field has long recognized intrinsic warhead reactivity as a key parameter to monitor, typically addressed by determining kinact and KI values, which are impractically time-intensive and can be misleading regarding reactivity. Here we present an alternative way to normalize potency for electrophilicity utilizing glutathione (GSH) consumption data, which enables us to extract target-specific improvements in potency, a metric we term ligand reactivity efficiency (LRE). Our hope is that the details of our approach and this metric will simplify the rational design of covalent drugs for fellow practitioners in the field.
{"title":"Normalizing Covalent Potency for Electrophilicity with Ligand Reactivity Efficiency.","authors":"Benjamin D Horning,Cian Kingston,Gabriel M Simon,Matthew P Patricelli,David S Weinstein,Brian N Cook","doi":"10.1021/acs.jmedchem.5c01803","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01803","url":null,"abstract":"Covalent modalities represent an important component of the modern medicinal chemist's toolbox for pursuing challenging targets in drug discovery. By taking a \"covalent-first\" approach to identifying druggable pockets on challenging-to-drug targets, we and others have expanded accessible target space and driven fragment-like hits to clinical-stage molecules. The field has long recognized intrinsic warhead reactivity as a key parameter to monitor, typically addressed by determining kinact and KI values, which are impractically time-intensive and can be misleading regarding reactivity. Here we present an alternative way to normalize potency for electrophilicity utilizing glutathione (GSH) consumption data, which enables us to extract target-specific improvements in potency, a metric we term ligand reactivity efficiency (LRE). Our hope is that the details of our approach and this metric will simplify the rational design of covalent drugs for fellow practitioners in the field.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"77 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147471836","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}
Alzheimer's disease impairs the cognitive domain of learning and memory through synaptic dysfunction. Memory formation requires gene expression to facilitate synaptic plasticity. When HDAC2 is inhibited, elevated histone acetylation promotes the gene expressions critical for synaptic plasticity and thus facilitates memory formation. However, simultaneous inhibition of HDAC1 and HDAC2 leads to hematologic toxicity. As the two isoforms have high homology, it is a challenge to identify selective HDAC2 inhibitors. Here, we report the development of novel cellular assays to determine HDAC2 potency and selectivity over HDAC1. Our HTS campaign using cellular assays for both isoforms identified 6 as a selective hit compound. With optimization efforts focusing on balancing cellular potency, selectivity, and mitigating BCRP recognition, we discovered compound 11, which exhibited significant in vivo efficacy in elevating histone acetylation levels and enhancing LTP. Importantly, 11 showed no significant hematological toxicity in human blood cells derived from simultaneous inhibition of HDAC1 and HDAC2.
{"title":"Discovery of Highly Selective HDAC2 Inhibitors in Cells That Elevate Histone Acetylation In Vivo without Adverse Effects from Dual Inhibition of HDAC1 and 2.","authors":"Naoyuki Suzuki,Hidekuni Yamakawa,Ken Yoshihara,Kazuki Niidome,Kosuke Anan,Kenji Takaya,Kensuke Kouki,Kazuki Fujimoto,Hiroko Ono,Takaya Izumi,Kazuhiro Unemura,Mana Ito,Takuya Hatta,Yasuto Kido,Naotaka Horiguchi,Ken-Ichi Kusakabe","doi":"10.1021/acs.jmedchem.5c02022","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02022","url":null,"abstract":"Alzheimer's disease impairs the cognitive domain of learning and memory through synaptic dysfunction. Memory formation requires gene expression to facilitate synaptic plasticity. When HDAC2 is inhibited, elevated histone acetylation promotes the gene expressions critical for synaptic plasticity and thus facilitates memory formation. However, simultaneous inhibition of HDAC1 and HDAC2 leads to hematologic toxicity. As the two isoforms have high homology, it is a challenge to identify selective HDAC2 inhibitors. Here, we report the development of novel cellular assays to determine HDAC2 potency and selectivity over HDAC1. Our HTS campaign using cellular assays for both isoforms identified 6 as a selective hit compound. With optimization efforts focusing on balancing cellular potency, selectivity, and mitigating BCRP recognition, we discovered compound 11, which exhibited significant in vivo efficacy in elevating histone acetylation levels and enhancing LTP. Importantly, 11 showed no significant hematological toxicity in human blood cells derived from simultaneous inhibition of HDAC1 and HDAC2.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"12 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147471835","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}
CD38 is an established biomarker for the diagnosis and treatment of various malignancies, including multiple myeloma. Accurate assessment of CD38 expression holds significant clinical value for optimizing CD38-targeted therapies. This study developed a series of small-molecule radiotracers for in vivo assessment of CD38 expression and monitoring of therapeutic response. All 68Ga-labeled radiotracers exhibited high radiochemical purity and stability both in vitro and in vivo. PET/CT imaging showed that 68Ga-NOTA-MK0159 uptake in multiple myeloma models correlated positively with CD38 expression and could be blocked by excess MK-0159. Notably, daratumumab did not block the uptake of 68Ga-NOTA-MK0159 under the experimental conditions of this study, suggesting the probe’s potential for assessing CD38 expression during daratumumab therapy. Preclinical studies demonstrated that 68Ga-NOTA-MK0159 enables noninvasive whole-body assessment of CD38 in multiple myeloma, which may guide personalized treatment and monitor CD38 expression during daratumumab therapy.
{"title":"CD38-Targeted Small-Molecule PET Radiotracer for Noninvasive Tumor Evaluation and Preliminary Therapy Monitoring in Multiple Myeloma","authors":"Chunyu Duan, Shibo Guo, Peng Xu, Wei Han, Yu Lu, Zhide Guo, Peng Fu, Gang Liu, Changjiu Zhao","doi":"10.1021/acs.jmedchem.5c03340","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03340","url":null,"abstract":"CD38 is an established biomarker for the diagnosis and treatment of various malignancies, including multiple myeloma. Accurate assessment of CD38 expression holds significant clinical value for optimizing CD38-targeted therapies. This study developed a series of small-molecule radiotracers for in vivo assessment of CD38 expression and monitoring of therapeutic response. All <sup>68</sup>Ga-labeled radiotracers exhibited high radiochemical purity and stability both in vitro and in vivo. PET/CT imaging showed that <sup>68</sup>Ga-NOTA-MK0159 uptake in multiple myeloma models correlated positively with CD38 expression and could be blocked by excess MK-0159. Notably, daratumumab did not block the uptake of <sup>68</sup>Ga-NOTA-MK0159 under the experimental conditions of this study, suggesting the probe’s potential for assessing CD38 expression during daratumumab therapy. Preclinical studies demonstrated that <sup>68</sup>Ga-NOTA-MK0159 enables noninvasive whole-body assessment of CD38 in multiple myeloma, which may guide personalized treatment and monitor CD38 expression during daratumumab therapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"36 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462116","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 : 2026-03-16DOI: 10.1021/acs.jmedchem.5c03050
Enrique Madruga, Alfonso Garcia-Rubia, Carlos Sanchez-Nuñez, Loreto Martinez-Gonzalez, Ana María Fernandez-Escamilla, Isabel Lastres-Becker, Carmen Gil, Ana Martinez
A major challenge in modern medicine is developing new therapies for aging-related diseases such as neurodegenerative disorders, whose prevalence increases with longer life expectancy. Although kinase inhibitors have achieved clinical success, their development for central nervous system (CNS) disorders remains limited due to the complexity of kinase networks and poor blood–brain barrier (BBB) permeability. Serum/glucocorticoid-regulated kinase 1 (SGK1) participates in multiple signaling pathways but remains an underexplored target in neurodegeneration. Following a mixed ligand- and structure-based virtual screening, we have previously identified a brain-penetrant SGK1 inhibitor. A medicinal chemistry program based on hit expansion and optimization for BBB permeability reported here has generated a new family of SGK1 inhibitors as chemical probes that enable the investigation of SGK1’s role in neurological disorders and serve as promising starting points for drug development. These findings highlight SGK1 as a potential therapeutic target for neurodegenerative diseases, such as Alzheimer’s disease.
{"title":"Brain Permeable SGK1 Inhibitors: A Promising Therapeutic Strategy for Neurodegenerative Diseases","authors":"Enrique Madruga, Alfonso Garcia-Rubia, Carlos Sanchez-Nuñez, Loreto Martinez-Gonzalez, Ana María Fernandez-Escamilla, Isabel Lastres-Becker, Carmen Gil, Ana Martinez","doi":"10.1021/acs.jmedchem.5c03050","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03050","url":null,"abstract":"A major challenge in modern medicine is developing new therapies for aging-related diseases such as neurodegenerative disorders, whose prevalence increases with longer life expectancy. Although kinase inhibitors have achieved clinical success, their development for central nervous system (CNS) disorders remains limited due to the complexity of kinase networks and poor blood–brain barrier (BBB) permeability. Serum/glucocorticoid-regulated kinase 1 (SGK1) participates in multiple signaling pathways but remains an underexplored target in neurodegeneration. Following a mixed ligand- and structure-based virtual screening, we have previously identified a brain-penetrant SGK1 inhibitor. A medicinal chemistry program based on hit expansion and optimization for BBB permeability reported here has generated a new family of SGK1 inhibitors as chemical probes that enable the investigation of SGK1’s role in neurological disorders and serve as promising starting points for drug development. These findings highlight SGK1 as a potential therapeutic target for neurodegenerative diseases, such as Alzheimer’s disease.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"44 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462172","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 : 2026-03-16DOI: 10.1021/acs.jmedchem.5c03280
Antonio Linero-Artiaga, Marie Svitelova, Vojtěch Novohradský, Venancio Rodríguez, Lenka Markova, Jana Kasparkova, Christoph Janiak, José Ruiz, Viktor Brabec
This study explores the therapeutic potential of seven bis-cyclometalated Ir(III) complexes (1–7), derived from the 2,2′-(benzothiazolyl)benzimidazole scaffold, as highly promising next-generation photoactivatable agents for type I and type II-guided photodynamic therapy (PDT) in lung and colorectal cancers. Their high phototoxicity in 2D and 3D cancer cell models, achieving IC50 values in the nanomolar region, was closely linked to the generation of singlet oxygen and type I reactive oxygen species (ROS) and the photooxidation of NADH, with complex 4 identified as the strongest ROS inducer and the most photocytotoxic complex. Notably, the iridium complexes proved to maintain their phototoxicity in hypoxic conditions. Using 3D spheroids, complex 4 demonstrated deep tissue penetration sought to overcome PDT limitations in solid tumors. Overall, the synthesized complexes showcase high efficacy and favorable pharmacological profiles, positioning them as promising candidates for the ROS-guided photodynamic treatment of cancers, including those located within hypoxic environments.
{"title":"Novel 2-(2′-Benzothiazolyl)-benzimidazole-Based Iridium(III) Photocatalysts Exhibit Antiproliferative Effects in 2D and 3D Cancer Cells to Bypass Hypoxia-Induced Resistance","authors":"Antonio Linero-Artiaga, Marie Svitelova, Vojtěch Novohradský, Venancio Rodríguez, Lenka Markova, Jana Kasparkova, Christoph Janiak, José Ruiz, Viktor Brabec","doi":"10.1021/acs.jmedchem.5c03280","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03280","url":null,"abstract":"This study explores the therapeutic potential of seven bis-cyclometalated Ir(III) complexes (<b>1–7</b>), derived from the 2,2′-(benzothiazolyl)benzimidazole scaffold, as highly promising next-generation photoactivatable agents for type I and type II-guided photodynamic therapy (PDT) in lung and colorectal cancers. Their high phototoxicity in 2D and 3D cancer cell models, achieving IC<sub>50</sub> values in the nanomolar region, was closely linked to the generation of singlet oxygen and type I reactive oxygen species (ROS) and the photooxidation of NADH, with complex <b>4</b> identified as the strongest ROS inducer and the most photocytotoxic complex. Notably, the iridium complexes proved to maintain their phototoxicity in hypoxic conditions. Using 3D spheroids, complex <b>4</b> demonstrated deep tissue penetration sought to overcome PDT limitations in solid tumors. Overall, the synthesized complexes showcase high efficacy and favorable pharmacological profiles, positioning them as promising candidates for the ROS-guided photodynamic treatment of cancers, including those located within hypoxic environments.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"93 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462173","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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