Journal of Medicinal Chemistry最新文献_第10页

The Medicinal Chemist’s Oath

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-03-13 DOI: 10.1021/acs.jmedchem.5c00619

Donald F. Weaver

引用次数: 0

Discovery of YJZ5118: A Potent and Highly Selective Irreversible CDK12/13 Inhibitor with Synergistic Effects in Combination with Akt Inhibition

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-03-13 DOI: 10.1021/acs.jmedchem.5c0012710.1021/acs.jmedchem.5c00127

Jianzhang Yang, Yu Chang, Kaijie Zhou, Weixue Huang, Jean Ching-Yi Tien, Pujuan Zhang, Wenyan Liu, Licheng Zhou, Yang Zhou, Xiaomei Ren, Rahul Mannan, Somnath Mahapatra, Yuping Zhang, Rudana Hamadeh, Grafton Ervine, Zhen Wang*, George Xiaoju Wang*, Arul M. Chinnaiyan* and Ke Ding*,

{"title":"Discovery of YJZ5118: A Potent and Highly Selective Irreversible CDK12/13 Inhibitor with Synergistic Effects in Combination with Akt Inhibition","authors":"Jianzhang Yang, Yu Chang, Kaijie Zhou, Weixue Huang, Jean Ching-Yi Tien, Pujuan Zhang, Wenyan Liu, Licheng Zhou, Yang Zhou, Xiaomei Ren, Rahul Mannan, Somnath Mahapatra, Yuping Zhang, Rudana Hamadeh, Grafton Ervine, Zhen Wang*, George Xiaoju Wang*, Arul M. Chinnaiyan* and Ke Ding*, ","doi":"10.1021/acs.jmedchem.5c0012710.1021/acs.jmedchem.5c00127","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00127https://doi.org/10.1021/acs.jmedchem.5c00127","url":null,"abstract":"Cyclin-dependent kinases 12 and 13 (CDK12/13) have emerged as promising therapeutic targets for castration-resistant prostate cancer (CRPC) and other human cancers. Despite the development of several CDK12/13 inhibitors, challenges remain in achieving an optimal balance of potency, selectivity and pharmacokinetic properties. Here, we report the discovery of YJZ5118, a novel, potent and highly selective covalent inhibitor of CDK12/13 with reasonable pharmacokinetic profiles. YJZ5118 effectively inhibited CDK12 and CDK13 with IC50 values of 39.5 and 26.4 nM, respectively, while demonstrating high selectivity over other CDKs. Mass spectrometry analysis, cocrystal structure determination, and pulldown-proteomic experiments confirmed the compound’s covalent binding mode with CDK12/13. Functionally, YJZ5118 efficiently suppressed the transcription of DNA damage response genes, induced DNA damage, and triggered apoptosis. Moreover, the compound significantly inhibited the proliferation of multiple tumor cell lines, particularly prostate cancer cells. Notably, YJZ5118 exhibited synergistic effects with Akt inhibitors both in vitro and in vivo.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 6","pages":"6718–6734 6718–6734"},"PeriodicalIF":6.8,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143703696","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}

引用次数: 0

Design of a Tetravalent RGD Peptide Capable of Simultaneous Binding with Multiple Integrin αvβ3 for Targeted Radionuclide Therapy

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-03-13 DOI: 10.1021/acs.jmedchem.4c03007

Yuki Mizuno, Thanakrit Suebboonprathueng, Satoru Onoe, Hiromichi Akizawa, Ken-ichi Nishijima, Kazuhiro Takahashi, Yuji Kuge

{"title":"Design of a Tetravalent RGD Peptide Capable of Simultaneous Binding with Multiple Integrin αvβ3 for Targeted Radionuclide Therapy","authors":"Yuki Mizuno, Thanakrit Suebboonprathueng, Satoru Onoe, Hiromichi Akizawa, Ken-ichi Nishijima, Kazuhiro Takahashi, Yuji Kuge","doi":"10.1021/acs.jmedchem.4c03007","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03007","url":null,"abstract":"For targeted radionuclide therapy, radioligands that exhibit high and persistent tumor uptake are indispensable. We previously synthesized a 99mTc-labeled hexavalent RGD peptide (99mTc-(RGD)6) as a tumor imaging agent targeting integrin αvβ3. 99mTc-(RGD)6 showed high in vivo tumor uptake with long retention due to simultaneous binding to multiple integrin αvβ3 receptors. The purpose of this study was to apply this finding to the design of a multivalent RGD peptide labeled with 211At, a promising α-emitting radionuclide for radionuclide therapy. As a candidate compound, a tetravalent RGD peptide (H2N-(RGD)4) was synthesized and radiolabeled with 125I, a homologous element of At, for basic studies. As expected, 125I-(RGD)4 retained the capability of simultaneous binding and showed comparable in vivo tumor uptake to 99mTc-(RGD)6. Finally, 211At-(RGD)4 was synthesized with >95% radiochemical purity and exhibited an almost identical biodistribution pattern to 125I-(RGD)4. These results indicate that 211At-(RGD)4 might be a potential radioligand for integrin αvβ3-targeted radionuclide therapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"55 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618979","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}

引用次数: 0

Biased Equilibrium Drives Cyclosporine Membrane Permeability: The Goldilocks Energy Barriers

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-03-12 DOI: 10.1021/acs.jmedchem.4c0317810.1021/acs.jmedchem.4c03178

Miranda N. Limbach, Edward T. Lindberg, Cynthiya Shrestha, Jinchao Lou, Carlos A. Steren, Michael D. Best and Thanh D. Do*,

{"title":"Biased Equilibrium Drives Cyclosporine Membrane Permeability: The Goldilocks Energy Barriers","authors":"Miranda N. Limbach, Edward T. Lindberg, Cynthiya Shrestha, Jinchao Lou, Carlos A. Steren, Michael D. Best and Thanh D. Do*, ","doi":"10.1021/acs.jmedchem.4c0317810.1021/acs.jmedchem.4c03178","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03178https://doi.org/10.1021/acs.jmedchem.4c03178","url":null,"abstract":"Conformational flexibility allows macrocyclic peptides like cyclosporine A (CycA) to cross membranes, yet drug design leveraging this property has largely failed. A key challenge is linking specific conformers to function, as different conformers govern permeability versus target binding. We reveal a mechanism that enhances CycA and alisporivir (ALI) permeability: trans-to-cis isomerization at MeVal11–MeBmt1 creates conformers that remain “soluble” in both membrane-like and aqueous environments. A biased equilibrium favors this conformer in protic environments, while a lipophilic conformer with cis MeLeu9–MeLeu10 dominates in aprotic conditions. This mechanism explains why CycH, Valspodar (VALSPO), and O-acetyl CycA (OAc-CycA) fail to cross membranes─they adopt similar states but lack this biased equilibrium. Our findings provide a new strategy for designing membrane-permeable N-methylated macrocycles and underscore the role of high-energy conformers as transition states between membrane permeability and target engagement─offering critical insights for drug development.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 6","pages":"6588–6600 6588–6600"},"PeriodicalIF":6.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143703823","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}

引用次数: 0

AI-Driven Discovery of Highly Specific and Efficacious hCES2A Inhibitors for Ameliorating Irinotecan-Triggered Gut Toxicity

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-03-12 DOI: 10.1021/acs.jmedchem.4c02560

Zhipei Sang, Ya Zhang, Yufan Fan, Changhai Luan, Zhengwei Liu, Qiyao Zhang, Hairong Zeng, Yunqing Song, Shuheng Huang, Guangbo Ge

{"title":"AI-Driven Discovery of Highly Specific and Efficacious hCES2A Inhibitors for Ameliorating Irinotecan-Triggered Gut Toxicity","authors":"Zhipei Sang, Ya Zhang, Yufan Fan, Changhai Luan, Zhengwei Liu, Qiyao Zhang, Hairong Zeng, Yunqing Song, Shuheng Huang, Guangbo Ge","doi":"10.1021/acs.jmedchem.4c02560","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02560","url":null,"abstract":"The anticancer agent irinotecan often induces severe delayed-onset diarrhea, inhibiting human carboxylesterase 2A (hCES2A) can significantly alleviate irinotecan-triggered gut toxicity (ITGT). This work presents an efficient workflow for de novo design and developing novel efficacious hCES2A inhibitors. A well-training machine learning model identified scaffold-14 as a lead compound, while compound 14n was developed as a novel time-dependent hCES2A inhibitor (IC50 = 0.04 nM) following three rounds of structural optimization. The covalent binding modes and inactivation mechanisms of 14n were elucidated by nanoLC-MS/MS-based chemoproteomics and covalent docking simulations. Notably, 14n showed excellent selectivity, good cell-membrane permeability, favorable drug-like properties, and potent inhibition on intracellular hCES2A. In vivo tests demonstrated that 14n was orally active, showing favorable safety profiles and impressive ameliorative effects on ITGT in tumor-bearing mice. Collectively, this work showcases a high-efficient AI-driven strategy for developing novel efficacious hCES2A inhibitors, while 14n emerges as a promising candidate for alleviating ITGT.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"87 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143600128","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}

引用次数: 0

Optimization of Cyclophilin B-Targeted Tri-vector Inhibitors for Novel MASH Treatments

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-03-12 DOI: 10.1021/acs.jmedchem.5c00301

Maria-Eleni Kouridaki, Jonathan Gillespie, John Robinson, Tanya Mathie, Laura Bain, Duncan McArthur, Angus Morrison, Daniel B. Greenslade, Michail Papadourakis, Kasia Maj, Kate Cameron, Darryl Turner, Scott P. Webster, Martin A. Wear, Dahlia Doughty-Shenton, Alison N. Hulme, Julien Michel

引用次数: 0

AI-Driven Discovery of Highly Specific and Efficacious hCES2A Inhibitors for Ameliorating Irinotecan-Triggered Gut Toxicity

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-03-12 DOI: 10.1021/acs.jmedchem.4c0256010.1021/acs.jmedchem.4c02560

Zhipei Sang, Ya Zhang, Yufan Fan, Changhai Luan, Zhengwei Liu, Qiyao Zhang, Hairong Zeng*, Yunqing Song*, Shuheng Huang* and Guangbo Ge*,

{"title":"AI-Driven Discovery of Highly Specific and Efficacious hCES2A Inhibitors for Ameliorating Irinotecan-Triggered Gut Toxicity","authors":"Zhipei Sang, Ya Zhang, Yufan Fan, Changhai Luan, Zhengwei Liu, Qiyao Zhang, Hairong Zeng*, Yunqing Song*, Shuheng Huang* and Guangbo Ge*, ","doi":"10.1021/acs.jmedchem.4c0256010.1021/acs.jmedchem.4c02560","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02560https://doi.org/10.1021/acs.jmedchem.4c02560","url":null,"abstract":"The anticancer agent irinotecan often induces severe delayed-onset diarrhea, inhibiting human carboxylesterase 2A (hCES2A) can significantly alleviate irinotecan-triggered gut toxicity (ITGT). This work presents an efficient workflow for de novo design and developing novel efficacious hCES2A inhibitors. A well-training machine learning model identified scaffold-14 as a lead compound, while compound 14n was developed as a novel time-dependent hCES2A inhibitor (IC50 = 0.04 nM) following three rounds of structural optimization. The covalent binding modes and inactivation mechanisms of 14n were elucidated by nanoLC-MS/MS-based chemoproteomics and covalent docking simulations. Notably, 14n showed excellent selectivity, good cell-membrane permeability, favorable drug-like properties, and potent inhibition on intracellular hCES2A. In vivo tests demonstrated that 14n was orally active, showing favorable safety profiles and impressive ameliorative effects on ITGT in tumor-bearing mice. Collectively, this work showcases a high-efficient AI-driven strategy for developing novel efficacious hCES2A inhibitors, while 14n emerges as a promising candidate for alleviating ITGT.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 6","pages":"6252–6269 6252–6269"},"PeriodicalIF":6.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143703822","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}

引用次数: 0

Biased Equilibrium Drives Cyclosporine Membrane Permeability: The Goldilocks Energy Barriers

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-03-12 DOI: 10.1021/acs.jmedchem.4c03178

Miranda N. Limbach, Edward T. Lindberg, Cynthiya Shrestha, Jinchao Lou, Carlos A. Steren, Michael D. Best, Thanh D. Do

{"title":"Biased Equilibrium Drives Cyclosporine Membrane Permeability: The Goldilocks Energy Barriers","authors":"Miranda N. Limbach, Edward T. Lindberg, Cynthiya Shrestha, Jinchao Lou, Carlos A. Steren, Michael D. Best, Thanh D. Do","doi":"10.1021/acs.jmedchem.4c03178","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03178","url":null,"abstract":"Conformational flexibility allows macrocyclic peptides like cyclosporine A (CycA) to cross membranes, yet drug design leveraging this property has largely failed. A key challenge is linking specific conformers to function, as different conformers govern permeability versus target binding. We reveal a mechanism that enhances CycA and alisporivir (ALI) permeability: trans-to-cis isomerization at MeVal11–MeBmt1 creates conformers that remain “soluble” in both membrane-like and aqueous environments. A biased equilibrium favors this conformer in protic environments, while a lipophilic conformer with cis MeLeu9–MeLeu10 dominates in aprotic conditions. This mechanism explains why CycH, Valspodar (VALSPO), and O-acetyl CycA (OAc-CycA) fail to cross membranes─they adopt similar states but lack this biased equilibrium. Our findings provide a new strategy for designing membrane-permeable N-methylated macrocycles and underscore the role of high-energy conformers as transition states between membrane permeability and target engagement─offering critical insights for drug development.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"49 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143608306","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}

引用次数: 0

Discovery of a Pyrazolopyridinone-Based MYC Inhibitor That Selectively Engages Intracellular c-MYC and Disrupts MYC–MAX Heterodimerization

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-03-12 DOI: 10.1021/acs.jmedchem.4c02556

Oluwatosin A. Obisesan, Samuel Ofori, Owamagbe N. Orobator, Himanshi Sharma, Emma Groetecke, Samuel G. Awuah

引用次数: 0

Discovery of a Pyrazolopyridinone-Based MYC Inhibitor That Selectively Engages Intracellular c-MYC and Disrupts MYC–MAX Heterodimerization

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-03-12 DOI: 10.1021/acs.jmedchem.4c0255610.1021/acs.jmedchem.4c02556

Oluwatosin A. Obisesan, Samuel Ofori, Owamagbe N. Orobator, Himanshi Sharma, Emma Groetecke and Samuel G. Awuah*,

{"title":"Discovery of a Pyrazolopyridinone-Based MYC Inhibitor That Selectively Engages Intracellular c-MYC and Disrupts MYC–MAX Heterodimerization","authors":"Oluwatosin A. Obisesan, Samuel Ofori, Owamagbe N. Orobator, Himanshi Sharma, Emma Groetecke and Samuel G. Awuah*, ","doi":"10.1021/acs.jmedchem.4c0255610.1021/acs.jmedchem.4c02556","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02556https://doi.org/10.1021/acs.jmedchem.4c02556","url":null,"abstract":"c-MYC is an oncogenic transcription factor that plays a crucial role in the regulation of downstream targets involved in proliferation, apoptosis, differentiation, metabolism, signaling, and immune response processes whose deregulation leads to the progression of different pathologies. The development of selective and potent small-molecule inhibitors of c-MYC remains a grand challenge in chemical biology and medicine due to its undruggability, derived from extensive intrinsic disorder. In this study, we identified a novel dihydro pyrazolo pyridinone scaffold, MY05, that selectively targets c-MYC in cells and disrupts MYC–MAX interaction. MY05 engages intracellular c-MYC, modulates c-MYC thermal stability, reduces c-MYC transcriptional targets, and inhibits proliferation in cancer cells and tumor growth in mice. In summary, we identified a novel compound that directly interacts with c-MYC to disrupt the transcriptional program.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 6","pages":"6233–6251 6233–6251"},"PeriodicalIF":6.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143703821","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}

引用次数: 0