Pub Date : 2026-10-19DOI: 10.1021/acs.jmedchem.6c01197
Dingpeng Zhang,Zhen Wang,William W. Feng,Wenyun Zhang,Xutong Xue,Yan Xiong,Xing Gao,Hiroyuki Inuzuka,Jeanelle Tsai,Jiaqi Li,Peiqiang Yan,Zhenbo Tu,Joao A. Paulo,H. Ümit Kaniskan,Antoine E. Karnoub,Pasi A. Jänne,Jian Jin,Wenyi Wei
Centromere protein B (CENPB), the only sequence-specific DNA-binding protein at centromeres, maintains chromosomal stability and accurate mitotic segregation. Its overexpression in aggressive cancers is associated with aneuploidy and poor prognosis, yet CENPB remains therapeutically underexplored because direct inhibitors are unavailable. Here, we develop CENPB OligoTAC, a DNA-based PROTAC comprising a CENPB-binding oligodeoxynucleotide linked to an E3 ligase ligand. CENPB OligoTAC induces ubiquitination and proteasomal degradation of CENPB, disrupting centromere integrity, causing chromosome mis-segregation, and activating apoptosis. It shows potent activity in preclinical non-small cell lung cancer models resistant to first-, second-, and third-generation tyrosine kinase inhibitors, while exhibiting minimal cytotoxicity toward normal cells and good serum stability. In vivo, CENPB OligoTAC demonstrates favorable pharmacokinetics, good tolerability, and no significant hematological changes. By exploiting cancer cells’ dependence on centromeric stability, this platform offers a novel strategy for selectively targeting aneuploid malignancies.
{"title":"Centromere-Targeting Chimeras for Combating Cancer Drug Resistance","authors":"Dingpeng Zhang,Zhen Wang,William W. Feng,Wenyun Zhang,Xutong Xue,Yan Xiong,Xing Gao,Hiroyuki Inuzuka,Jeanelle Tsai,Jiaqi Li,Peiqiang Yan,Zhenbo Tu,Joao A. Paulo,H. Ümit Kaniskan,Antoine E. Karnoub,Pasi A. Jänne,Jian Jin,Wenyi Wei","doi":"10.1021/acs.jmedchem.6c01197","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01197","url":null,"abstract":"Centromere protein B (CENPB), the only sequence-specific DNA-binding protein at centromeres, maintains chromosomal stability and accurate mitotic segregation. Its overexpression in aggressive cancers is associated with aneuploidy and poor prognosis, yet CENPB remains therapeutically underexplored because direct inhibitors are unavailable. Here, we develop CENPB OligoTAC, a DNA-based PROTAC comprising a CENPB-binding oligodeoxynucleotide linked to an E3 ligase ligand. CENPB OligoTAC induces ubiquitination and proteasomal degradation of CENPB, disrupting centromere integrity, causing chromosome mis-segregation, and activating apoptosis. It shows potent activity in preclinical non-small cell lung cancer models resistant to first-, second-, and third-generation tyrosine kinase inhibitors, while exhibiting minimal cytotoxicity toward normal cells and good serum stability. In vivo, CENPB OligoTAC demonstrates favorable pharmacokinetics, good tolerability, and no significant hematological changes. By exploiting cancer cells’ dependence on centromeric stability, this platform offers a novel strategy for selectively targeting aneuploid malignancies.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"7 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218802","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 : 2026-10-19DOI: 10.1021/acs.jmedchem.6c01710
Vanessa M. Marx,Anne-Catherine Mata,Fumiaki Yokokawa,Thomas Kirrane,Richard Huang,Suresh B. Lakshminarayana,Jay Prakash Jain,Judith Straimer,W. Armand Guiguemde,Luying Pei,Upendra Kulkarni,Christopher J. Thompson,Johanna M. Jansen,Patrick S. Lee,Eric J. Martin,Valery R. Polyakov,Nicole Blaquiere,Alexander Burckle,Grace Waldron,Benjamin R. Taft,Erika L. Flannery,Hanna Schulz,Qumber H. Jafri,Katherine Chan,Erika Kim,Harry Cheung,Vida Ahyong,Changbok Lee,Catherine L. Jones,Christopher S. Lunde,Iñigo Angulo-Barturen,María Belén Jiménez-Díaz,Leyre Pernaute-Lau,Christian Scheurer,Sibylle Sax,Sergio Wittlin,Anna Caroline Campos Aguiar,Rafael Victorio Carvalho Guido,Dhelio B. Pereira,Philip J. Rosenthal,Roland A. Cooper,Kyra A. Schindler,David A. Fidock,Brice Campo,Simon F. Campbell,Thierry T. Diagana,Christopher R. Sarko
Malaria remains a major cause of morbidity and mortality, particularly among young children, in endemic regions such as sub-Saharan Africa and Southeast Asia. Moreover, the emerging resistance of Plasmodium parasites to front-line therapeutics underscores the need for new blood-stage antimalarial drugs. Utilizing a Plasmodium falciparum (Pf) growth inhibition assay, we identified a novel pyrazine-2-carboxamide series. Lead optimization improved anti-plasmodial potency, metabolic stability, and reduced CYP2D6 inhibition risk, leading to the selection of IWY357 (1). A single dose of 100 mg per kg (mpk) is fully curative in a Pf-humanized severe combined immunodeficient mouse model (TADhuMouse®-Pfalc), and IWY357 (1) also exhibits a high barrier to resistance in drug selection studies. Given the significant potential to provide a curative therapy for uncomplicated malaria with short dosing regimens, either alone or in combination, IWY357 (1) was progressed through GLP toxicology studies into phase 1 clinical trials.
在撒哈拉以南非洲和东南亚等流行区域，疟疾仍然是发病和死亡的一个主要原因，特别是在幼儿中。此外，疟原虫对一线治疗药物的新耐药性强调了开发新的血期抗疟药物的必要性。利用恶性疟原虫（Pf）生长抑制试验，我们鉴定了一种新的吡嗪-2-羧酰胺系列。铅优化提高了抗疟原虫效力、代谢稳定性，降低了CYP2D6抑制风险，最终选择了IWY357(1)。单剂量100 mg / kg （mpk）在pf人源化严重联合免疫缺陷小鼠模型（TADhuMouse®-Pfalc）中完全治愈，IWY357(1)在药物选择研究中也显示出高耐药屏障。考虑到IWY357(1)具有巨大的潜力，可以用短剂量方案单独或联合治疗无并发症的疟疾，IWY357(1)已通过GLP毒理学研究进入1期临床试验。
{"title":"Discovery of a Pyrazine-2-Carboxamide Derivative as a Potent Plasmodium falciparum Inhibitor with Potential for Single-Dose Cure","authors":"Vanessa M. Marx,Anne-Catherine Mata,Fumiaki Yokokawa,Thomas Kirrane,Richard Huang,Suresh B. Lakshminarayana,Jay Prakash Jain,Judith Straimer,W. Armand Guiguemde,Luying Pei,Upendra Kulkarni,Christopher J. Thompson,Johanna M. Jansen,Patrick S. Lee,Eric J. Martin,Valery R. Polyakov,Nicole Blaquiere,Alexander Burckle,Grace Waldron,Benjamin R. Taft,Erika L. Flannery,Hanna Schulz,Qumber H. Jafri,Katherine Chan,Erika Kim,Harry Cheung,Vida Ahyong,Changbok Lee,Catherine L. Jones,Christopher S. Lunde,Iñigo Angulo-Barturen,María Belén Jiménez-Díaz,Leyre Pernaute-Lau,Christian Scheurer,Sibylle Sax,Sergio Wittlin,Anna Caroline Campos Aguiar,Rafael Victorio Carvalho Guido,Dhelio B. Pereira,Philip J. Rosenthal,Roland A. Cooper,Kyra A. Schindler,David A. Fidock,Brice Campo,Simon F. Campbell,Thierry T. Diagana,Christopher R. Sarko","doi":"10.1021/acs.jmedchem.6c01710","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01710","url":null,"abstract":"Malaria remains a major cause of morbidity and mortality, particularly among young children, in endemic regions such as sub-Saharan Africa and Southeast Asia. Moreover, the emerging resistance of Plasmodium parasites to front-line therapeutics underscores the need for new blood-stage antimalarial drugs. Utilizing a Plasmodium falciparum (Pf) growth inhibition assay, we identified a novel pyrazine-2-carboxamide series. Lead optimization improved anti-plasmodial potency, metabolic stability, and reduced CYP2D6 inhibition risk, leading to the selection of IWY357 (1). A single dose of 100 mg per kg (mpk) is fully curative in a Pf-humanized severe combined immunodeficient mouse model (TADhuMouse®-Pfalc), and IWY357 (1) also exhibits a high barrier to resistance in drug selection studies. Given the significant potential to provide a curative therapy for uncomplicated malaria with short dosing regimens, either alone or in combination, IWY357 (1) was progressed through GLP toxicology studies into phase 1 clinical trials.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"12 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218804","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}
Abstract Acute pancreatitis (AP) is a sterile inflammatory disease characterized by aberrant zymogen activation, tissue autodigestion, and cross-amplifying inflammatory cascades that complicate targeted therapies. Our single-cell transcriptomics analysis revealed early NOD1 pathway activation in pancreatic acinar and ductal cells in cerulein-induced AP mice, suggesting potential involvement across these cell types. Here, through a scaffold-hopping strategy, we obtained novel-scaffold NOD1 antagonists. Further optimization yielded 32q and its highly water-soluble disodium salt, 32q-2Na. They exhibited low-nanomolar potency against NOD1 with high selectivity. 32q-2Na pharmacologically inhibited NOD1 signaling, significantly reducing serum levels of amylase (AMY), lipase (LIP), MCP-1, and IL-6, and markedly attenuating pancreatic inflammatory responses in cerulein- and FAEE-induced murine models of AP. In conclusion, these findings establish NOD1 as a highly tractable upstream regulatory node for AP intervention.
{"title":"A Novel Small-Molecule Antagonist of the NOD1 Signaling Pathway as a Therapeutic Strategy for Acute Pancreatitis","authors":"Xinhua Liu,Dan Wang,Yuting Wang,Nan Zhang,Xiduan Wei,Shiping Fang,Shengtao Zhu,Yao Ma,Wenjun Yu,Gang Liu","doi":"10.1021/acs.jmedchem.6c02155","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02155","url":null,"abstract":"Abstract Acute pancreatitis (AP) is a sterile inflammatory disease characterized by aberrant zymogen activation, tissue autodigestion, and cross-amplifying inflammatory cascades that complicate targeted therapies. Our single-cell transcriptomics analysis revealed early NOD1 pathway activation in pancreatic acinar and ductal cells in cerulein-induced AP mice, suggesting potential involvement across these cell types. Here, through a scaffold-hopping strategy, we obtained novel-scaffold NOD1 antagonists. Further optimization yielded 32q and its highly water-soluble disodium salt, 32q-2Na. They exhibited low-nanomolar potency against NOD1 with high selectivity. 32q-2Na pharmacologically inhibited NOD1 signaling, significantly reducing serum levels of amylase (AMY), lipase (LIP), MCP-1, and IL-6, and markedly attenuating pancreatic inflammatory responses in cerulein- and FAEE-induced murine models of AP. In conclusion, these findings establish NOD1 as a highly tractable upstream regulatory node for AP intervention.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"25 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210193","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}
Abstract Antibiotic resistance poses a serious threat to human health. Inspired by the clinical practice of employing drug combinations to achieve combined effects, we hypothesized that integrating multiple mechanisms into a single molecule could address drug-resistant bacterial infections. Based on a propeller-modification strategy and dual alkyl-chain engineering, we de novo designed and synthesized a C2-symmetric propeller-shaped aggregation-induced emission photosensitizer. After iterative screening, the optimized compound MeOTDP-2 exhibits broad-spectrum antibacterial activity, enabling efficient eradication of planktonic bacteria, drug-resistant strains, polymicrobial infections, biofilms, and persister cells, with no cellular invasiveness and negligible cytotoxicity. Mechanistic studies revealed that MeOTDP-2 achieves chemo-photodynamic combined antibacterial therapy by targeting and disrupting bacterial membranes and DNA, alongside light-mediated intracellular reactive oxygen species accumulation. Furthermore, in mouse models of MRSA-induced skin abscess and full-thickness skin wound infection, MeOTDP-2 demonstrated superior therapeutic efficacy to vancomycin. This strategy, integrating dual targeting with multiple mechanisms, offers new promise for overcoming bacterial resistance.
{"title":"De Novo\u0000 Design of Multi-Mechanistic AIE Photosensitizer for Broad-Spectrum Bacterial Eradication","authors":"Zhi-Hao Li,Yi-Qiong Sun,Daran Li,Kai-Wei Zhu,Shuya Chen,Luyang Xue,Xuehua Liu,Ruirui Li,Hongtao Kong,Yin-Chao Li,En Zhang","doi":"10.1021/acs.jmedchem.6c02325","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02325","url":null,"abstract":"Abstract Antibiotic resistance poses a serious threat to human health. Inspired by the clinical practice of employing drug combinations to achieve combined effects, we hypothesized that integrating multiple mechanisms into a single molecule could address drug-resistant bacterial infections. Based on a propeller-modification strategy and dual alkyl-chain engineering, we de novo designed and synthesized a C2-symmetric propeller-shaped aggregation-induced emission photosensitizer. After iterative screening, the optimized compound MeOTDP-2 exhibits broad-spectrum antibacterial activity, enabling efficient eradication of planktonic bacteria, drug-resistant strains, polymicrobial infections, biofilms, and persister cells, with no cellular invasiveness and negligible cytotoxicity. Mechanistic studies revealed that MeOTDP-2 achieves chemo-photodynamic combined antibacterial therapy by targeting and disrupting bacterial membranes and DNA, alongside light-mediated intracellular reactive oxygen species accumulation. Furthermore, in mouse models of MRSA-induced skin abscess and full-thickness skin wound infection, MeOTDP-2 demonstrated superior therapeutic efficacy to vancomycin. This strategy, integrating dual targeting with multiple mechanisms, offers new promise for overcoming bacterial resistance.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"11 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210246","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 : 2026-10-18DOI: 10.1021/acs.jmedchem.6c02247
Li Zhang,Pan Tang,Yun Xu,Cheng Cheng,Gaofeng Zhu,Lei Tang
Abstract Intestinal farnesoid X receptor (FXR) antagonism has emerged as a strategy to enhance endogenous glucagon-like peptide-1 (GLP-1) secretion and improve metabolic control in type 2 diabetes mellitus (T2DM). Dihydrooleanolic acid methyl ester (DKS26) served as the scaffold for the synthesis of 64 pentacyclic triterpene derivatives modified at the terminal carboxyl group and C-3/C-12 positions. Esterification of the terminal carboxylate emerged as a determinant of FXR antagonism, identifying 4l bearing a tetrazole-containing side chain and C-12 hydroxyl motif. Compound 4l antagonized FXR in a TR-FRET assay (IC50 = 11.79 μM), a fivefold improvement over DKS26. In NCI-H716 cells, 4l reduced NR0B2 (SHP) mRNA expression and markedly stimulated GLP-1 secretion. In HFD/STZ-induced diabetic mice, oral 4l improved glycemia, increased circulating GLP-1 and insulin, and alleviated dyslipidemia and organ injury markers. These findings establish the pentacyclic triterpene scaffold as a platform for FXR antagonism and identify 4l as a lead for further optimization.
{"title":"Design, Synthesis, and Biological Evaluation of Pentacyclic Triterpene Derivatives as Intestinal FXR Antagonists for Type 2 Diabetes","authors":"Li Zhang,Pan Tang,Yun Xu,Cheng Cheng,Gaofeng Zhu,Lei Tang","doi":"10.1021/acs.jmedchem.6c02247","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02247","url":null,"abstract":"Abstract Intestinal farnesoid X receptor (FXR) antagonism has emerged as a strategy to enhance endogenous glucagon-like peptide-1 (GLP-1) secretion and improve metabolic control in type 2 diabetes mellitus (T2DM). Dihydrooleanolic acid methyl ester (DKS26) served as the scaffold for the synthesis of 64 pentacyclic triterpene derivatives modified at the terminal carboxyl group and C-3/C-12 positions. Esterification of the terminal carboxylate emerged as a determinant of FXR antagonism, identifying 4l bearing a tetrazole-containing side chain and C-12 hydroxyl motif. Compound 4l antagonized FXR in a TR-FRET assay (IC50 = 11.79 μM), a fivefold improvement over DKS26. In NCI-H716 cells, 4l reduced NR0B2 (SHP) mRNA expression and markedly stimulated GLP-1 secretion. In HFD/STZ-induced diabetic mice, oral 4l improved glycemia, increased circulating GLP-1 and insulin, and alleviated dyslipidemia and organ injury markers. These findings establish the pentacyclic triterpene scaffold as a platform for FXR antagonism and identify 4l as a lead for further optimization.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"4 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210340","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 : 2026-10-18DOI: 10.1021/acs.jmedchem.6c02803
Min An,Yuting Dai,Le Ma,Lu Yang,Jiahui Ma,Yangbing Li,Yaping Ma,Long Qin,Zhijian Han
Oligonucleotide therapeutics have emerged as next-generation therapeutics. However, targeted delivery of oligonucleotides to extrahepatic tissues, such as skeletal and cardiac muscles and the central nervous system, at efficacious yet well-tolerated doses remain a major challenge for their clinical translation. Although antibody−oligonucleotide conjugates are promising for the treatment of genetic disorders, inadequate tissue penetration and immunogenicity have constrained their therapeutic efficacy. By combining the advantages of cell-penetrating peptides (CPPs) or cell-targeting peptides (CTPs) with those of oligonucleotides, peptide−oligonucleotide conjugates (POCs) display enhanced cellular uptake, endosomal escape, and extrahepatic delivery. The therapeutic efficacy of POC was increased through conjugation with CPPs, endosomal-escape peptides (EEPs), fusogenic peptides, nuclear localization signal peptides, or CTPs. In this perspective, innovative molecular designs such as multivalent, cyclic, and chimeric peptides, and combinations of CPPs and EEPs, were explored, highlighting key advancements in POC development and providing insights into future directions for the development of novel POCs.
{"title":"Recent Advances in Peptide−Oligonucleotide Conjugates for Enhanced Therapeutic Efficacy","authors":"Min An,Yuting Dai,Le Ma,Lu Yang,Jiahui Ma,Yangbing Li,Yaping Ma,Long Qin,Zhijian Han","doi":"10.1021/acs.jmedchem.6c02803","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02803","url":null,"abstract":"Oligonucleotide therapeutics have emerged as next-generation therapeutics. However, targeted delivery of oligonucleotides to extrahepatic tissues, such as skeletal and cardiac muscles and the central nervous system, at efficacious yet well-tolerated doses remain a major challenge for their clinical translation. Although antibody−oligonucleotide conjugates are promising for the treatment of genetic disorders, inadequate tissue penetration and immunogenicity have constrained their therapeutic efficacy. By combining the advantages of cell-penetrating peptides (CPPs) or cell-targeting peptides (CTPs) with those of oligonucleotides, peptide−oligonucleotide conjugates (POCs) display enhanced cellular uptake, endosomal escape, and extrahepatic delivery. The therapeutic efficacy of POC was increased through conjugation with CPPs, endosomal-escape peptides (EEPs), fusogenic peptides, nuclear localization signal peptides, or CTPs. In this perspective, innovative molecular designs such as multivalent, cyclic, and chimeric peptides, and combinations of CPPs and EEPs, were explored, highlighting key advancements in POC development and providing insights into future directions for the development of novel POCs.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"11 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210903","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 : 2026-10-18DOI: 10.1021/acs.jmedchem.6c01450
Megan J. Jurek,Christian J. Peters,Andrew P. Riley
Neuropathic pain remains a significant clinical challenge due to the varying efficacies and aversive effects associated with the currently available treatments. Most notably, the addiction potential associated with opioid use for pain presents a critical need for non-opioid-targeting analgesics. In the last two decades, α9-containing nicotinic acetylcholine receptors (nAChRs) have been evaluated preclinically for their potential as a new target for neuropathic pain therapies. In this perspective, we discuss several classes of ligands that modulate these receptors, highlighting hurdles that have arisen during their development and efforts that have been made to improve their therapeutic potential. Additionally, we consider the significant role these ligands have played in current and future drug discovery for this target.
{"title":"Ligands Targeting α9-Containing Nicotinic Acetylcholine Receptors: Structure−Activity Relationships and Therapeutic Potential in Neuropathic Pain","authors":"Megan J. Jurek,Christian J. Peters,Andrew P. Riley","doi":"10.1021/acs.jmedchem.6c01450","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01450","url":null,"abstract":"Neuropathic pain remains a significant clinical challenge due to the varying efficacies and aversive effects associated with the currently available treatments. Most notably, the addiction potential associated with opioid use for pain presents a critical need for non-opioid-targeting analgesics. In the last two decades, α9-containing nicotinic acetylcholine receptors (nAChRs) have been evaluated preclinically for their potential as a new target for neuropathic pain therapies. In this perspective, we discuss several classes of ligands that modulate these receptors, highlighting hurdles that have arisen during their development and efforts that have been made to improve their therapeutic potential. Additionally, we consider the significant role these ligands have played in current and future drug discovery for this target.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"33 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210904","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 : 2026-10-18DOI: 10.1021/acs.jmedchem.6c02769
Debora Chiodi,Yoshihiro Ishihara
Abstract The tert-butyl group is a large substituent that could be useful in some contexts for filling protein pockets, but this highly lipophilic group typically worsens the ADMET properties of the parent scaffold. Although many bioisosteres of tert-butyl are similarly lipophilic, gem-dimethylcarbinol could be a bioisostere with greatly reduced lipophilicity, bestowing balanced properties to a lead compound. This could benefit multi-parameter optimization that includes solubility, permeability, and in vitro clearance. Although one downside of installing the gem-dimethylcarbinol group is greater efflux, making it a poor motif for CNS applications, small structural modifications could mitigate this issue. The gem-dimethylcarbinol group is not chemically reactive under physiological conditions, is not a blacklisted toxicophore, and is present in a small but growing number of approved drugs. Furthermore, the simplicity of its installation in organic chemistry makes it an attractive option as a tert-butyl bioisostere with great opportunities in medicinal chemistry.
{"title":"gem\u0000 -Dimethylcarbinol: A\u0000 tert\u0000 -Butyl Bioisostere with Greatly Reduced Lipophilicity","authors":"Debora Chiodi,Yoshihiro Ishihara","doi":"10.1021/acs.jmedchem.6c02769","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02769","url":null,"abstract":"Abstract The tert-butyl group is a large substituent that could be useful in some contexts for filling protein pockets, but this highly lipophilic group typically worsens the ADMET properties of the parent scaffold. Although many bioisosteres of tert-butyl are similarly lipophilic, gem-dimethylcarbinol could be a bioisostere with greatly reduced lipophilicity, bestowing balanced properties to a lead compound. This could benefit multi-parameter optimization that includes solubility, permeability, and in vitro clearance. Although one downside of installing the gem-dimethylcarbinol group is greater efflux, making it a poor motif for CNS applications, small structural modifications could mitigate this issue. The gem-dimethylcarbinol group is not chemically reactive under physiological conditions, is not a blacklisted toxicophore, and is present in a small but growing number of approved drugs. Furthermore, the simplicity of its installation in organic chemistry makes it an attractive option as a tert-butyl bioisostere with great opportunities in medicinal chemistry.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"71 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210194","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 : 2026-10-18DOI: 10.1021/acs.jmedchem.6c01914
Farinaz Soleymani,Ganga Reddy Velma,Zhengnan Shen,Cameron Holberg,Jiqiang Fu,Divakar Reddy Indukuri,Soumya Reddy Musku,Elizaveta Lazarova,Steve Slilaty,Zuomei Li,Kiira Ratia,Rui Xiong,Gregory R. J. Thatcher
Abstract The papain-like protease (PLpro) of SARS-CoV-2, essential for viral processing and immune evasion, is a promising therapeutic target for coronavirus infections. Incorporating strategies used to enhance activity of non-covalent inhibitors, notably engagement of the BL2-groove, remote from the active site Cys-111, covalent PLpro inhibitors were designed. Epoxysuccinamide inhibitors demonstrated subnanomolar potency and 107-fold reduction in viral titer in cell cultures. The flexible hydrazide linker required for reaction of Cys-111 with the epoxysuccinamide warhead was susceptible to hepatic carboxylesterase metabolism. Replacement of hydrazide with alternative linkers was unsuccessful. Administered i.v., an epoxysuccinamide was well tolerated in mice. Although metabolically limited for targeting SARS-CoV-2 PLpro, the warhead was validated as a potent tool in the armamentarium of antivirals to confront emerging viruses.
{"title":"Discovery of Epoxysuccinates as Potent Covalent Inhibitors of SARS-CoV-2 Papain-like Protease","authors":"Farinaz Soleymani,Ganga Reddy Velma,Zhengnan Shen,Cameron Holberg,Jiqiang Fu,Divakar Reddy Indukuri,Soumya Reddy Musku,Elizaveta Lazarova,Steve Slilaty,Zuomei Li,Kiira Ratia,Rui Xiong,Gregory R. J. Thatcher","doi":"10.1021/acs.jmedchem.6c01914","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01914","url":null,"abstract":"Abstract The papain-like protease (PLpro) of SARS-CoV-2, essential for viral processing and immune evasion, is a promising therapeutic target for coronavirus infections. Incorporating strategies used to enhance activity of non-covalent inhibitors, notably engagement of the BL2-groove, remote from the active site Cys-111, covalent PLpro inhibitors were designed. Epoxysuccinamide inhibitors demonstrated subnanomolar potency and 107-fold reduction in viral titer in cell cultures. The flexible hydrazide linker required for reaction of Cys-111 with the epoxysuccinamide warhead was susceptible to hepatic carboxylesterase metabolism. Replacement of hydrazide with alternative linkers was unsuccessful. Administered i.v., an epoxysuccinamide was well tolerated in mice. Although metabolically limited for targeting SARS-CoV-2 PLpro, the warhead was validated as a potent tool in the armamentarium of antivirals to confront emerging viruses.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"12 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210192","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 : 2026-10-18DOI: 10.1021/acs.jmedchem.6c00563
Aleksandra Leśniewska,Adam Buczkowski,Piotr Ruszkowski,Matthew J. Binder,Alison D. Axtman,Wojciech Schilf,Ewelina Smolarz,Krystian Pyta,Maria Gdaniec,Franz J. Bartl,Piotr Przybylski
To reduce toxicity of geldanamycin (GDM), the domino transformation of its benzoquinone core into benzoxazole has been performed. Structural studies of ester-phenol and ester-ether benzoxazole-type ansamycins indicate that the former is present as (Sp)-diastereomer, whereas the latter is present as conformation-“locked” (Rp)-diastereomer, which is more favorable at binding to Hsp90. Several of the obtained benzoxazole ansamycins revealed high anticancer potency in SKBr-3, MCF-7, SKOV-3, and PC-3 lines with improved selectivity and lower affinity to glutathione, compared to GDM. The most potent derivative 6 reveals excellent anticancer activity (IC50 < 0.6 μM) with Hsp90 as the primary target [KD6-Hsp90 = 0.3 μM], limited off-target effects (kinases), and decreased toxicity (selectivity indices = 2.75−3.48) regarding GDM. Ester-ether type derivative 22 reveals good anticancer potency in SKOV-3 (IC50 = 0.62 μM) with reduced toxicity in human dermal fibroblast and human umbilical vein endothelial cells, improved selectivity (SISKOV-3 = 2.75), apoptotic index AISKOV-3 ∼8, and high chemical and in vivo stabilities.
{"title":"Cascade Mono- and Di-Functionalization of Anticancer Diastereomeric Benzoxazole-Ansamycins toward the Development of Highly Potent Hsp90 Inhibitors of Decreased Toxicity in Normal Cells","authors":"Aleksandra Leśniewska,Adam Buczkowski,Piotr Ruszkowski,Matthew J. Binder,Alison D. Axtman,Wojciech Schilf,Ewelina Smolarz,Krystian Pyta,Maria Gdaniec,Franz J. Bartl,Piotr Przybylski","doi":"10.1021/acs.jmedchem.6c00563","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c00563","url":null,"abstract":"To reduce toxicity of geldanamycin (GDM), the domino transformation of its benzoquinone core into benzoxazole has been performed. Structural studies of ester-phenol and ester-ether benzoxazole-type ansamycins indicate that the former is present as (Sp)-diastereomer, whereas the latter is present as conformation-“locked” (Rp)-diastereomer, which is more favorable at binding to Hsp90. Several of the obtained benzoxazole ansamycins revealed high anticancer potency in SKBr-3, MCF-7, SKOV-3, and PC-3 lines with improved selectivity and lower affinity to glutathione, compared to GDM. The most potent derivative 6 reveals excellent anticancer activity (IC50 < 0.6 μM) with Hsp90 as the primary target [KD6-Hsp90 = 0.3 μM], limited off-target effects (kinases), and decreased toxicity (selectivity indices = 2.75−3.48) regarding GDM. Ester-ether type derivative 22 reveals good anticancer potency in SKOV-3 (IC50 = 0.62 μM) with reduced toxicity in human dermal fibroblast and human umbilical vein endothelial cells, improved selectivity (SISKOV-3 = 2.75), apoptotic index AISKOV-3 ∼8, and high chemical and in vivo stabilities.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"42 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210914","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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