Cyclin-dependent kinase 7 (CDK7) is a promising cancer therapeutic target due to its dual role in cell cycle progression and gene transcription. However, current CDK7 inhibitors generally exhibit poor kinase selectivity. Herein, we performed in-depth structural optimization on a 17-membered macrocyclic scaffold, and identified compound I-23, which potently inhibits CDK7 with an IC50 value of 3 nM and exhibits exceptional CDK7 selectivity with no significant off-target activity across 416 kinases. I-23 also potently inhibits cell proliferation across a panel of tumor cell lines, induces cell cycle arrest and transcriptional suppression, and downregulates oncoprotein c-Myc, particularly in triple-negative breast cancer cells. Importantly, I-23 shows favorable oral bioavailability (up to 28%) with linear pharmacokinetics. Collectively, this work provides a highly selective and orally bioavailable macrocyclic CDK7 inhibitor, which can serve as a valuable chemical tool for dissecting CDK7 biological functions and a promising lead compound for CDK7-based anticancer drug discovery.
{"title":"Discovery of Pyrazolo[1,5-a]-1,3,5-Triazine Derivatives as Potent, Highly Selective and Orally Available Macrocyclic CDK7 Inhibitors","authors":"Quanpeng Wei,Yanxin Tao,Xinpeng Ning,Suyun Jia,Yan Chen,Xiaoli Du,Xinyu Sun,Lingrui Xu,Xinrui Jiang,Pengpeng Niu,Mengyang Fan,Yupeng Li,Dawei Ma,Shan Li,Ke Ding","doi":"10.1021/acs.jmedchem.6c01660","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01660","url":null,"abstract":"Cyclin-dependent kinase 7 (CDK7) is a promising cancer therapeutic target due to its dual role in cell cycle progression and gene transcription. However, current CDK7 inhibitors generally exhibit poor kinase selectivity. Herein, we performed in-depth structural optimization on a 17-membered macrocyclic scaffold, and identified compound I-23, which potently inhibits CDK7 with an IC50 value of 3 nM and exhibits exceptional CDK7 selectivity with no significant off-target activity across 416 kinases. I-23 also potently inhibits cell proliferation across a panel of tumor cell lines, induces cell cycle arrest and transcriptional suppression, and downregulates oncoprotein c-Myc, particularly in triple-negative breast cancer cells. Importantly, I-23 shows favorable oral bioavailability (up to 28%) with linear pharmacokinetics. Collectively, this work provides a highly selective and orally bioavailable macrocyclic CDK7 inhibitor, which can serve as a valuable chemical tool for dissecting CDK7 biological functions and a promising lead compound for CDK7-based anticancer drug discovery.","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":"149221698","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}
Targeted protein degradation has transformed drug discovery by enabling selective elimination of disease-associated proteins. Beyond classical E3 ligase-recruiting degraders, emerging proteasome-directed strategies seek to recruit targets directly to the proteasome, potentially bypassing E3 ligase dependency and ubiquitination requirements. This approach may expand the degradable proteome, but requires proteasome ligands that engage accessible surfaces, tolerate linker attachment, and preserve basal proteasome function. In this Perspective, we summarize recent advances in direct proteasome-targeting degradation, focusing on ligands of the 19S regulatory particle and 20S core particle. We assess how proteasome subunits and binding pockets have been exploited for degrader design and distinguish ligand-level challenges, such as undefined binding sites, immature SAR, and uncertain linker vectors, from degrader-level issues, including cellular exposure, degradation selectivity, off-target effects, and proteostasis liability. These considerations provide a framework for designing next-generation proteasome-recruiting degraders.
{"title":"From Ubiquitination to Proteasome-Directed Recruiting: Emerging Mechanisms and Therapeutic Potential in Targeted Protein Degradation","authors":"Yaoli Shi,Jiayi Ma,Yutong Tu,Qingyi Wang,Mingzhi Wang,Jiaan Shao,Guifeng Wang,Jia Li,Huajian Zhu,Yubo Zhou,Jiankang Zhang","doi":"10.1021/acs.jmedchem.6c01098","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01098","url":null,"abstract":"Targeted protein degradation has transformed drug discovery by enabling selective elimination of disease-associated proteins. Beyond classical E3 ligase-recruiting degraders, emerging proteasome-directed strategies seek to recruit targets directly to the proteasome, potentially bypassing E3 ligase dependency and ubiquitination requirements. This approach may expand the degradable proteome, but requires proteasome ligands that engage accessible surfaces, tolerate linker attachment, and preserve basal proteasome function. In this Perspective, we summarize recent advances in direct proteasome-targeting degradation, focusing on ligands of the 19S regulatory particle and 20S core particle. We assess how proteasome subunits and binding pockets have been exploited for degrader design and distinguish ligand-level challenges, such as undefined binding sites, immature SAR, and uncertain linker vectors, from degrader-level issues, including cellular exposure, degradation selectivity, off-target effects, and proteostasis liability. These considerations provide a framework for designing next-generation proteasome-recruiting degraders.","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":"149221741","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.6c02108
Shikha Kumari,Krishnaiah Maddeboina,Shiva Hadi Esfahani,Shirisha Jonnalagadda,Xiaoyu Hao,Aarfa Queen,Yong Zhang,Asmaa Aly,Haya Kandil,Saeideh Nozohouri,Hossam Elaraky,Thomas J. Abbruscato,Vardan T. Karamyan,Paul C. Trippier
The peptidase neurolysin (Nln) is upregulated following ischemic stroke to activate endogenous cerebroprotective mechanisms and has subsequently emerged as a therapeutic target for drug discovery efforts. Overexpression of Nln in a mouse model of ischemic stroke results in significant improvement of stroke outcomes. Herein, we report the discovery of the first non-peptide Nln activators based around a central pyridine-piperazine scaffold that possesses nanomolar potency. This scaffold, exemplified by compounds 7c and 7g, exhibits greater in vitro half-life, blood−brain barrier penetration, mouse brain and mouse plasma stability than previously reported peptidomimetic Nln activators. Compound 7g afforded an in vivo protective effect in the MCAO mouse model of ischemic stroke, significantly reducing infarct volume and brain water content, marking the first report of a small molecule Nln activator with in vivo cerebroprotective effects in a preclinical model.
{"title":"Discovery of Neurolysin Activators with Preclinical Efficacy in an Ischemic Stroke Model","authors":"Shikha Kumari,Krishnaiah Maddeboina,Shiva Hadi Esfahani,Shirisha Jonnalagadda,Xiaoyu Hao,Aarfa Queen,Yong Zhang,Asmaa Aly,Haya Kandil,Saeideh Nozohouri,Hossam Elaraky,Thomas J. Abbruscato,Vardan T. Karamyan,Paul C. Trippier","doi":"10.1021/acs.jmedchem.6c02108","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02108","url":null,"abstract":"The peptidase neurolysin (Nln) is upregulated following ischemic stroke to activate endogenous cerebroprotective mechanisms and has subsequently emerged as a therapeutic target for drug discovery efforts. Overexpression of Nln in a mouse model of ischemic stroke results in significant improvement of stroke outcomes. Herein, we report the discovery of the first non-peptide Nln activators based around a central pyridine-piperazine scaffold that possesses nanomolar potency. This scaffold, exemplified by compounds 7c and 7g, exhibits greater in vitro half-life, blood−brain barrier penetration, mouse brain and mouse plasma stability than previously reported peptidomimetic Nln activators. Compound 7g afforded an in vivo protective effect in the MCAO mouse model of ischemic stroke, significantly reducing infarct volume and brain water content, marking the first report of a small molecule Nln activator with in vivo cerebroprotective effects in a preclinical model.","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":"149221746","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}
Fibroblast activation protein (FAP) is an attractive target for radiotheranostic development because of its abundant expression in tumor-associated fibroblasts and limited distribution in normal tissues. Here, we developed FAP-Man, a mannosylated FAP-targeted radioglycopeptide based on the FAP-2286 scaffold, to optimize tumor targeting and pharmacokinetic properties. Compared with [68Ga]Ga-FAP-2286, [68Ga]Ga-FAP-Man showed higher tumor uptake in U87MG tumor-bearing mice (16.917 ± 4.986 vs 3.188 ± 0.535 %ID/g at 1 h post-injection) and improved tumor-to-liver contrast. Both [177Lu]Lu-FAP-Man and [225Ac]Ac-FAP-Man significantly inhibited tumor growth compared with PBS-treated controls. Preliminary clinical PET imaging further supported its potential for favorable lesion visualization and lesion-to-background contrast, particularly for hepatic lesions. These findings support further evaluation of FAP-Man as a FAP-targeted radiopharmaceutical candidate.
成纤维细胞活化蛋白（FAP）在肿瘤相关成纤维细胞中大量表达，而在正常组织中的分布有限，因此成为放射治疗发展的一个有吸引力的靶标。在这里，我们开发了FAP-Man，一种基于FAP-2286支架的甘露糖基化fap靶向放射糖肽，以优化肿瘤靶向性和药代动力学特性。与[68Ga]Ga-FAP-2286相比，[68Ga]Ga-FAP-Man在U87MG荷瘤小鼠中表现出更高的肿瘤摄取（注射后1 h为16.917±4.986 vs 3.188±0.535 %ID/g），并改善了肿瘤到肝脏的对比。与pbs处理的对照组相比，[177Lu]Lu-FAP-Man和[225Ac]Ac-FAP-Man均能显著抑制肿瘤生长。初步的临床PET成像进一步支持其潜在的有利病变可视化和病变背景对比，特别是肝脏病变。这些发现支持进一步评价FAP-Man作为fap靶向放射性药物的候选药物。
{"title":"Design and Biological Evaluation of FAP-Man, a Mannosylated FAP-Targeted Radioglycopeptide for Tumor Imaging and Radionuclide Therapy","authors":"Miaomiao Song,Entao Liu,Rui Cao,Luming Sun,Peng Wang,Shuang Duan,Ji Tao,Long Qiu,Jin Du,Ning Liu,Feize Li,Chunrong Qu,Lei Jiang,Zhen Cheng","doi":"10.1021/acs.jmedchem.6c02436","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02436","url":null,"abstract":"Fibroblast activation protein (FAP) is an attractive target for radiotheranostic development because of its abundant expression in tumor-associated fibroblasts and limited distribution in normal tissues. Here, we developed FAP-Man, a mannosylated FAP-targeted radioglycopeptide based on the FAP-2286 scaffold, to optimize tumor targeting and pharmacokinetic properties. Compared with [68Ga]Ga-FAP-2286, [68Ga]Ga-FAP-Man showed higher tumor uptake in U87MG tumor-bearing mice (16.917 ± 4.986 vs 3.188 ± 0.535 %ID/g at 1 h post-injection) and improved tumor-to-liver contrast. Both [177Lu]Lu-FAP-Man and [225Ac]Ac-FAP-Man significantly inhibited tumor growth compared with PBS-treated controls. Preliminary clinical PET imaging further supported its potential for favorable lesion visualization and lesion-to-background contrast, particularly for hepatic lesions. These findings support further evaluation of FAP-Man as a FAP-targeted radiopharmaceutical candidate.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"16 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221749","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}
Six-transmembrane epithelial antigen of prostate 2 (STEAP2) is overexpressed in prostate cancer, yet no STEAP2-targeted imaging probes exist. Using molecular docking, we screened triptorelin and leuprorelin by radioiodine labeling and identified triptorelin as a high-affinity, selective ligand. To enhance in vivo stability and pharmacokinetics, triptorelin underwent acetylation, PEG extension, and 4-iodophenylbutyric acid conjugation, yielding five DOTA-conjugated analogs radiolabeled with 68Ga. In 22Rv1 xenografts, 68Ga-Trip-5 exhibited moderate but specific tumor uptake (SUVmax 1.8) with favorable tumor-to-background contrast. In vivo stability, biodistribution, pharmacokinetics, and human radiation dosimetry (effective dose 0.00345 mSv/MBq) demonstrated favorable safety. Autoradiography on human prostate cancer specimens showed probe accumulation correlating with endogenous STEAP2 expression. This represents the first STEAP2-targeted PET probe developed via molecular docking-guided drug repurposing. Cellular, biochemical, and imaging data provide supportive evidence of STEAP2-mediated targeting. Preclinical performance supports clinical translation of 68Ga-Trip-5, with definitive target validation
{"title":"Development and Preclinical Evaluation of Six-Transmembrane Epithelial Antigen of Prostate 2 Targeted PET Probes: A Case of Drug Repurposing Based on Molecular Docking","authors":"Zhuoyi Deng,Wenyuan Zhou,Chen Liu,Chao Liu,Honglei Zhang,Yifei Pei,Lulin Yang,Hua Zhu,Zhi Yang,Teli Liu","doi":"10.1021/acs.jmedchem.6c01270","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01270","url":null,"abstract":"Six-transmembrane epithelial antigen of prostate 2 (STEAP2) is overexpressed in prostate cancer, yet no STEAP2-targeted imaging probes exist. Using molecular docking, we screened triptorelin and leuprorelin by radioiodine labeling and identified triptorelin as a high-affinity, selective ligand. To enhance in vivo stability and pharmacokinetics, triptorelin underwent acetylation, PEG extension, and 4-iodophenylbutyric acid conjugation, yielding five DOTA-conjugated analogs radiolabeled with 68Ga. In 22Rv1 xenografts, 68Ga-Trip-5 exhibited moderate but specific tumor uptake (SUVmax 1.8) with favorable tumor-to-background contrast. In vivo stability, biodistribution, pharmacokinetics, and human radiation dosimetry (effective dose 0.00345 mSv/MBq) demonstrated favorable safety. Autoradiography on human prostate cancer specimens showed probe accumulation correlating with endogenous STEAP2 expression. This represents the first STEAP2-targeted PET probe developed via molecular docking-guided drug repurposing. Cellular, biochemical, and imaging data provide supportive evidence of STEAP2-mediated targeting. Preclinical performance supports clinical translation of 68Ga-Trip-5, with definitive target validation","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"45 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221762","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.6c02347
Weiqi Liu,Minhao Liang,Taiwei Chu
Radioiodinated drugs face limited application due to severe in vivo deiodination. In this study, nine tyrosine derivatives were synthesized and evaluated to develop stable radioiodinated prosthetic groups to reduce deiodination. Biodistribution results revealed that replacing phenolic hydroxyl and amino groups with methoxy and acetamide groups enhanced stability. Compound 131I-8 exhibited the highest stability, with a maximum thyroid uptake of 1.13 ± 0.12 %ID (approximately one-20th of 131I-Tyr). It’s high stability was explained by in vitro stability experiments and molecular docking. A new PSMA-targeted radioiodinated drug, [125/131I]IMPA, was synthesized to verify whether compound 8 remained stable after conjugation with drugs. It exhibited a lower thyroid uptake of only 0.19 ± 0.03 %ID, approximately 100-fold lower than that of the control compound [131I]ITPA, which has a tyrosine moiety as the radioiodination site. In conclusion, 8 is a small, easily labeled, and highly stable prosthetic group with promising potential for developing stable radioiodinated drugs and broadening their therapeutic application.
{"title":"Synthesis and In Vitro/In Vivo Stability Evaluation of Various Radioiodinated Tyrosine Derivatives","authors":"Weiqi Liu,Minhao Liang,Taiwei Chu","doi":"10.1021/acs.jmedchem.6c02347","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02347","url":null,"abstract":"Radioiodinated drugs face limited application due to severe in vivo deiodination. In this study, nine tyrosine derivatives were synthesized and evaluated to develop stable radioiodinated prosthetic groups to reduce deiodination. Biodistribution results revealed that replacing phenolic hydroxyl and amino groups with methoxy and acetamide groups enhanced stability. Compound 131I-8 exhibited the highest stability, with a maximum thyroid uptake of 1.13 ± 0.12 %ID (approximately one-20th of 131I-Tyr). It’s high stability was explained by in vitro stability experiments and molecular docking. A new PSMA-targeted radioiodinated drug, [125/131I]IMPA, was synthesized to verify whether compound 8 remained stable after conjugation with drugs. It exhibited a lower thyroid uptake of only 0.19 ± 0.03 %ID, approximately 100-fold lower than that of the control compound [131I]ITPA, which has a tyrosine moiety as the radioiodination site. In conclusion, 8 is a small, easily labeled, and highly stable prosthetic group with promising potential for developing stable radioiodinated drugs and broadening their therapeutic application.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"34 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221696","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.6c01880
Buyu Kou,Mengxiao Zhuang,Tong Song,Xin Liu,Chao Peng,Haixia Liu,Mingliang Wang,Xun Sun
Although TNF-α is a clinically validated target for Ulcerative colitis (UC), therapy is dominated by injectable biologics, with no oral small-molecule inhibitors approved. Traditional ATP-competitive p38 inhibitors designed to regulate TNF-α have failed in clinical trials due to poor kinome selectivity. As the primary upstream activator of p38, MKK3 is considered a promising alternative target, but the development of small molecules remains limited, with a notable absence of non-ATP-competitive modulators. Herein, we report a series of compounds targeting the non-ATP-competitive pocket of MKK3 to suppress TNF-α production. Among them, (R)-48 was identified as a lead candidate, demonstrating robust suppression of TNF-α (IC50: 0.038 μM), high oral bioavailability (62.6%), clear dose-dependent efficacy and strong PK/PD relationships in mouse UC models. Particularly, HDX-MS suggested (R)-48 probably binds to a distal allosteric site on MKK3, precluding TAK1-mediated activation. Altogether, (R)-48 emerges as a promising oral small-molecule therapeutic candidate for the treatment of UC.
{"title":"Design and Synthesis of Novel, Non-ATP-Competitive MKK3 Modulators as Suppressors of TNF-α Production for the Treatment of Ulcerative Colitis","authors":"Buyu Kou,Mengxiao Zhuang,Tong Song,Xin Liu,Chao Peng,Haixia Liu,Mingliang Wang,Xun Sun","doi":"10.1021/acs.jmedchem.6c01880","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01880","url":null,"abstract":"Although TNF-α is a clinically validated target for Ulcerative colitis (UC), therapy is dominated by injectable biologics, with no oral small-molecule inhibitors approved. Traditional ATP-competitive p38 inhibitors designed to regulate TNF-α have failed in clinical trials due to poor kinome selectivity. As the primary upstream activator of p38, MKK3 is considered a promising alternative target, but the development of small molecules remains limited, with a notable absence of non-ATP-competitive modulators. Herein, we report a series of compounds targeting the non-ATP-competitive pocket of MKK3 to suppress TNF-α production. Among them, (R)-48 was identified as a lead candidate, demonstrating robust suppression of TNF-α (IC50: 0.038 μM), high oral bioavailability (62.6%), clear dose-dependent efficacy and strong PK/PD relationships in mouse UC models. Particularly, HDX-MS suggested (R)-48 probably binds to a distal allosteric site on MKK3, precluding TAK1-mediated activation. Altogether, (R)-48 emerges as a promising oral small-molecule therapeutic candidate for the treatment of UC.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"34 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221761","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.6c01963
Jacqueline H. Starrett,Daniel C. Bensen,Ronald V. Swanson,Robert L. Hudkins
Fibroblast growth factor receptor 3 (FGFR3) gain-of-function alterations drive a spectrum of conditions, including cancers and skeletal dysplasias, making FGFR3 an attractive therapeutic target. While second-generation pan-FGFR inhibitors established clinical proof-of-concept, their utility has been constrained by toxicities associated with inhibition of FGFR1, FGFR2, and FGFR4. Despite the high degree of structural homology within the FGFR family, structure-guided medicinal chemistry efforts have recently enabled the development of the first FGFR3-selective inhibitors to enter clinical evaluation. These agents are now being investigated for indications including bladder cancer and achondroplasia. Improved isoform selectivity has the potential to enhance tolerability, enable more durable target inhibition, and expand the therapeutic application of FGFR3-directed therapies. In this Perspective, we discuss the biological rationale for selective FGFR3 inhibition, the structure-based design strategies that have enabled FGFR3 selectivity, and emerging clinical opportunities to address unmet needs in FGFR3-driven disease.
{"title":"FGFR3 Selectivity in Drug Discovery: Biological Rationale, Design Strategies, and Therapeutic Potential","authors":"Jacqueline H. Starrett,Daniel C. Bensen,Ronald V. Swanson,Robert L. Hudkins","doi":"10.1021/acs.jmedchem.6c01963","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01963","url":null,"abstract":"Fibroblast growth factor receptor 3 (FGFR3) gain-of-function alterations drive a spectrum of conditions, including cancers and skeletal dysplasias, making FGFR3 an attractive therapeutic target. While second-generation pan-FGFR inhibitors established clinical proof-of-concept, their utility has been constrained by toxicities associated with inhibition of FGFR1, FGFR2, and FGFR4. Despite the high degree of structural homology within the FGFR family, structure-guided medicinal chemistry efforts have recently enabled the development of the first FGFR3-selective inhibitors to enter clinical evaluation. These agents are now being investigated for indications including bladder cancer and achondroplasia. Improved isoform selectivity has the potential to enhance tolerability, enable more durable target inhibition, and expand the therapeutic application of FGFR3-directed therapies. In this Perspective, we discuss the biological rationale for selective FGFR3 inhibition, the structure-based design strategies that have enabled FGFR3 selectivity, and emerging clinical opportunities to address unmet needs in FGFR3-driven disease.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"28 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218807","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}
Herein, the synthesis and characterization of four new water-soluble pincer-copper complexes of the type (R2NNN)CuCl2 (R = C6H5, p-OMe-C6H4, p-Me-C6H4, and p-F-C6H4) based on bis(imino)pyridine ligands have been reported. The complexes exhibited significant cytotoxicity against a monolayer of MCF-7 breast cancer cells following light irradiation. Notably, the complex (Ph2NNN)CuCl2 demonstrated the highest efficacy among the pincer-Cu complexes, with an IC50 of 11 μM in the presence of light and an IC50 of 25 μM in dark conditions, making it ideal for photodynamic therapy (PDT). The complex (Ph2NNN)CuCl2 demonstrated selectivity for MCF-7 cells, as indicated by its reduced cytotoxicity against HEK cells. The generation of singlet oxygen (1O2) led to photo-oxidation-mediated apoptosis, as evidenced by the Annexin V/PI assay and concomitant G2/M cell cycle arrest. Furthermore, cleaved PARP (cPARP) expression upon photoactivation also confirmed the induction of apoptosis. This work provides an avenue for future applications of strategically engineered water-soluble pincer-metal complexes in cancer phototherapy.
{"title":"Evaluation of Cytotoxic Potential of Water-Soluble Photosensitive Pincer-Copper Complexes","authors":"Hachina Begum,Babu Venkateshappa,Hirakjyoti Roy,Siddhartha Sankar Ghosh,Akshai Kumar","doi":"10.1021/acs.jmedchem.6c02129","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02129","url":null,"abstract":"Herein, the synthesis and characterization of four new water-soluble pincer-copper complexes of the type (R2NNN)CuCl2 (R = C6H5, p-OMe-C6H4, p-Me-C6H4, and p-F-C6H4) based on bis(imino)pyridine ligands have been reported. The complexes exhibited significant cytotoxicity against a monolayer of MCF-7 breast cancer cells following light irradiation. Notably, the complex (Ph2NNN)CuCl2 demonstrated the highest efficacy among the pincer-Cu complexes, with an IC50 of 11 μM in the presence of light and an IC50 of 25 μM in dark conditions, making it ideal for photodynamic therapy (PDT). The complex (Ph2NNN)CuCl2 demonstrated selectivity for MCF-7 cells, as indicated by its reduced cytotoxicity against HEK cells. The generation of singlet oxygen (1O2) led to photo-oxidation-mediated apoptosis, as evidenced by the Annexin V/PI assay and concomitant G2/M cell cycle arrest. Furthermore, cleaved PARP (cPARP) expression upon photoactivation also confirmed the induction of apoptosis. This work provides an avenue for future applications of strategically engineered water-soluble pincer-metal complexes in cancer phototherapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"44 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218806","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.6c02207
Tara Man Kadayat,Gaurav Shoeran,Daniel C. Scott,Kristin L. Begley,Jared T. Hammill,Jong Yeon Hwang,Tucker J. Moseley,Ho Shin Kim,Agripina G. Deaciuc,Moeko T. King,Bhuvanesh Singh,Brenda A. Schulman,R. Kiplin Guy
We previously reported a potent and orally available inhibitor (2, NAcM-OPT) of the DCN1-UBE2M protein interaction that targets the neddylation pathway to potentially regulate oncogenic transformation for the treatment of cancer. In vivo profiling of compound 2 revealed that, while it was potent, orally bioavailable, and inhibited growth of tumor xenografts in immunodeficient mice, it possessed significant off-target affinity for the human ether-a-go-go-related gene protein (hERG Ki = 750 nM), thereby significantly limiting its potential for development. Herein, we disclose the rational and systematic modification of compound 2 to reduce the affinity for hERG while maintaining its affinity for and activity against DCN1. These studies led to the discovery of compound 110, which exhibited equivalent biochemical and cellular potency to 2, improved physicochemical properties, and increased selectivity relative to hERG.
我们之前报道了一种有效的口服DCN1-UBE2M蛋白相互作用抑制剂（2,NAcM-OPT），它靶向类化修饰途径，潜在地调节致癌转化，以治疗癌症。化合物2的体内分析显示，虽然它是有效的，口服生物利用度，并抑制免疫缺陷小鼠肿瘤异种移植物的生长，但它对人类醚-a-go-go相关基因蛋白（hERG Ki = 750 nM）具有显著的脱靶亲和力，从而显著限制了其发展潜力。在此，我们公开了化合物2的合理和系统的修饰，以降低对hERG的亲和力，同时保持其对DCN1的亲和力和活性。这些研究导致了化合物110的发现，它表现出与2相同的生化和细胞效力，改善了物理化学性质，并且相对于hERG增加了选择性。
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