Journal of Medicinal Chemistry最新文献_第5页

Novel Bioorthogonal Theranostic Scaffold Enables on-Target Drug Release and Real Time Monitoring In Vivo.

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-02-13 Epub Date: 2025-01-31 DOI: 10.1021/acs.jmedchem.4c02965

Jing Pang, Shun Feng, Bin Huang, Jujun Zhou, Linjun Zhan, Ya-Qiu Long

{"title":"Novel Bioorthogonal Theranostic Scaffold Enables on-Target Drug Release and Real Time Monitoring In Vivo.","authors":"Jing Pang, Shun Feng, Bin Huang, Jujun Zhou, Linjun Zhan, Ya-Qiu Long","doi":"10.1021/acs.jmedchem.4c02965","DOIUrl":"10.1021/acs.jmedchem.4c02965","url":null,"abstract":"Bioorthogonal chemistry-based prodrug strategy features spatiotemporally controlled release of therapeutic agent and/or imaging probe. However, the integration of diagnosis and therapy into a single molecule paired with a single bioorthogonal trigger remains a challenge. In this study, we devised a novel bioorthogonal theranostic scaffold amenable to the conjugation of various targeting agent and click-to-release reaction with the bioorthogonal prodrug to enable targeted drug liberation with concomitant fluorescence emission. Such one-stone-three-birds scaffold consists of a new fluorophore phenanthrodioxine (PDO) linked with a fluorescence masking group, tetrazine (Tz) which serves as a dual switch for the activation of fluorophore and drug. Further installation of a warhead of phenylboronic acid (PBA) ensures the targeted accumulation of the resultant PBA-PDO-Tz conjugate in tumor cells, thereby achieving on-demand activation of trans-cyclooctene-caged anticancer drug Doxorubicin with real-time monitoring and on-target cytotoxicity in live cells and an A549 xenograft mouse model. The targeted single trigger-dual response scaffold holds promise for precise theranostics applications in vivo.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":"3824-3836"},"PeriodicalIF":6.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062268","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

Quantitation and Error Measurements in Dose-Response Curves.

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-02-13 Epub Date: 2025-01-30 DOI: 10.1021/acs.jmedchem.5c00131

Bharath Srinivasan, Matthew D Lloyd

引用次数: 0

Correction to “Design, Synthesis, and Structure–Activity Relationship Study of Novel Indole-2-carboxamide Derivatives as Anti-inflammatory Agents for the Treatment of Sepsis”

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-02-13 DOI: 10.1021/acs.jmedchem.5c00203

Zhiguo Liu, Longguang Tang, Heping Zhu, Tingting Xu, Chenyu Qiu, Suqing Zheng, Yugui Gu, Jianpeng Feng, Yali Zhang, Guang Liang

引用次数: 0

Design of Selective BRD4 Inhibitors for the Treatment of Autosomal Dominant Polycystic Kidney Disease

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-02-13 DOI: 10.1021/acs.jmedchem.4c02128

Yueyue Yang, Hongli Liu, Haoxing Yuan, Kaikai Lyu, Haiyang Zhong, Yanlian Li, Danyan Cao, Wenchao Zhao, Haoran Zhang, Bing Xiong, Danqi Chen, Dong Guo

{"title":"Design of Selective BRD4 Inhibitors for the Treatment of Autosomal Dominant Polycystic Kidney Disease","authors":"Yueyue Yang, Hongli Liu, Haoxing Yuan, Kaikai Lyu, Haiyang Zhong, Yanlian Li, Danyan Cao, Wenchao Zhao, Haoran Zhang, Bing Xiong, Danqi Chen, Dong Guo","doi":"10.1021/acs.jmedchem.4c02128","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02128","url":null,"abstract":"Epigenetic modulation plays a pivotal role in restraining tumor progression by governing gene expression and protein function. Autosomal dominant polycystic kidney disease (ADPKD), characterized by neoplastic-like progression, can be managed by inhibiting cyst expansion. Of note, the epigenetic regulator BRD4 has been implicated in ADPKD’s development. Our prior research unveiled a class of (pyrazol-3-yl) pyrimidin-4-amine compounds as potent BRD4 inhibitors with additional kinase inhibition, which might induce unwanted biological activities. To address this, this study focused on creating selective BRD4 inhibitors through structure-guided design, minimizing off-target kinase interactions. Specifically, compound 23 emerged as an efficacious and selective BRD4 inhibitor in cellular and embryonic kidney models of ADPKD, along with encouraging outcomes in murine models. Collectively, these results highlight the therapeutic potential of targeted BRD4 inhibition as a safe and efficacious strategy for managing ADPKD.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"16 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401887","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 Diphenyl Ether Derivatives as Novel BK_Ca Channel Activators: Structure-Activity Relationship, Cryo-EM Complex Structures, and In Vivo Animal Studies.

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-02-13 DOI: 10.1021/acs.jmedchem.4c02008

Soo Bin Park, Na Young Lee, Eun-Young Lee, Subin Kim, Narasaem Lee, Eun Chae Roh, Yoon Gyoon Kim, Hee Jin Kim, Mi Sun Jin, Chul-Seung Park, Yong-Chul Kim

{"title":"Discovery of Diphenyl Ether Derivatives as Novel BKCa Channel Activators: Structure-Activity Relationship, Cryo-EM Complex Structures, and In Vivo Animal Studies.","authors":"Soo Bin Park, Na Young Lee, Eun-Young Lee, Subin Kim, Narasaem Lee, Eun Chae Roh, Yoon Gyoon Kim, Hee Jin Kim, Mi Sun Jin, Chul-Seung Park, Yong-Chul Kim","doi":"10.1021/acs.jmedchem.4c02008","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02008","url":null,"abstract":"The BKCa channel, a large-conductance calcium-activated potassium channel, plays a crucial role in maintaining the homeostasis of the micturition cycle and airway-related functions. In this study, we optimized a novel BKCa channel activator, 4d, with a diphenyl ether structure identified from library screening. This led to the discovery of potent activators, 10b (EC50 = 0.12 μM, cell-based assay) and 51b, an orally bioavailable derivative. Compound 10b demonstrated potent in vivo efficacy in a spontaneous hypertensive rat (SHR) of urinary incontinence model, while compound 51b showed dose-dependent cough suppression efficacy with an ED50 of 11.8 mg/kg in a citric acid-induced cough model. Furthermore, we reported the cryo-electron microscopy (cryo-EM) structures of the BKCa channel in complex with 10b and 51b at resolutions of 2.8 and 3.4 Å. Based on structural analyses, we determined the binding sites and key interaction residues of 51b, which were validated via mutation studies.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412364","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

Medicinal Chemistry Reviews, Volume 59.

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-02-13 Epub Date: 2025-01-31 DOI: 10.1021/acs.jmedchem.5c00157

Joachim Rudolph, William J Watkins

引用次数: 0

Discovery of First Branched-Chain Ketoacid Dehydrogenase Kinase (BDK) Inhibitor Clinical Candidate PF-07328948. 发现首个支链酮酸脱氢酶（BDK）抑制剂临床候选药物 PF-07328948。

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-02-13 Epub Date: 2024-11-19 DOI: 10.1021/acs.jmedchem.4c02230

Kevin J Filipski, Luis A Martinez-Alsina, Matthew R Reese, Edelweiss Evrard, Leanne M Buzon, Kimberly O Cameron, Yuan Zhang, Karen J Coffman, James Bradow, Bethany L Kormos, Shenping Liu, John D Knafels, Parag V Sahasrabudhe, Jie Chen, Amit S Kalgutkar, Andrew J Bessire, Christine C Orozco, Amanda Balesano, Matthew A Cerny, Eliza Bollinger, Allan R Reyes, Brigitte Laforest, Amy Rosado, George Williams, Mackenzie Marshall, Kelly Tam Neale, Xian Chen, Dinesh Hirenallur-Shanthappa, John C Stansfield, John Groarke, Ruolun Qiu, Spinel Karas, Rachel J Roth Flach, William P Esler

{"title":"Discovery of First Branched-Chain Ketoacid Dehydrogenase Kinase (BDK) Inhibitor Clinical Candidate PF-07328948.","authors":"Kevin J Filipski, Luis A Martinez-Alsina, Matthew R Reese, Edelweiss Evrard, Leanne M Buzon, Kimberly O Cameron, Yuan Zhang, Karen J Coffman, James Bradow, Bethany L Kormos, Shenping Liu, John D Knafels, Parag V Sahasrabudhe, Jie Chen, Amit S Kalgutkar, Andrew J Bessire, Christine C Orozco, Amanda Balesano, Matthew A Cerny, Eliza Bollinger, Allan R Reyes, Brigitte Laforest, Amy Rosado, George Williams, Mackenzie Marshall, Kelly Tam Neale, Xian Chen, Dinesh Hirenallur-Shanthappa, John C Stansfield, John Groarke, Ruolun Qiu, Spinel Karas, Rachel J Roth Flach, William P Esler","doi":"10.1021/acs.jmedchem.4c02230","DOIUrl":"10.1021/acs.jmedchem.4c02230","url":null,"abstract":"Inhibition of branched-chain ketoacid dehydrogenase kinase (BDK or BCKDK), a negative regulator of branched-chain amino acid (BCAA) metabolism, is hypothesized to treat cardio-metabolic diseases. From a starting point with potential idiosyncratic toxicity risk, modification to a benzothiophene core and discovery of a cryptic pocket allowed for improved potency with 3-aryl substitution to arrive at PF-07328948, which was largely devoid of protein covalent binding liability. This BDK inhibitor was shown also to be a BDK degrader in cells and in vivo rodent studies. Plasma biomarkers, including BCAAs and branched-chain ketoacids (BCKAs), were lowered in vivo with enhanced pharmacodynamic effect upon chronic dosing due to BDK degradation. This molecule improves metabolic and heart failure end points in rodent models. PF-07328948 is the first known selective BDK inhibitor candidate to be examined in clinical studies, with Phase 1 single ascending dose data showing good tolerability and a pharmacokinetic profile commensurate with once-daily dosing.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":"2466-2482"},"PeriodicalIF":6.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666220","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

Rational Design and Optimization of a Potent IDO1 Proteolysis Targeting Chimera (PROTAC).

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-02-13 DOI: 10.1021/acs.jmedchem.5c00026

Paige J Monsen, Prashant V Bommi, Arabela A Grigorescu, Kristen L Lauing, Yingyu Mao, Payton Berardi, Lijie Zhai, Oluwatomilayo Ojo, Manon Penco-Campillo, Taylor Koch, Michael Egozi, Sonam Jha, Sara F Dunne, Hong Jiang, Guiqin Song, Fang Zhang, Steven Kregel, Ali Vaziri-Gohar, Sean W Fanning, Pilar Sanchez-Gomez, Jacob M Allen, Bakhtiar Yamini, Rimas V Lukas, Derek A Wainwright, Gary E Schiltz

{"title":"Rational Design and Optimization of a Potent IDO1 Proteolysis Targeting Chimera (PROTAC).","authors":"Paige J Monsen, Prashant V Bommi, Arabela A Grigorescu, Kristen L Lauing, Yingyu Mao, Payton Berardi, Lijie Zhai, Oluwatomilayo Ojo, Manon Penco-Campillo, Taylor Koch, Michael Egozi, Sonam Jha, Sara F Dunne, Hong Jiang, Guiqin Song, Fang Zhang, Steven Kregel, Ali Vaziri-Gohar, Sean W Fanning, Pilar Sanchez-Gomez, Jacob M Allen, Bakhtiar Yamini, Rimas V Lukas, Derek A Wainwright, Gary E Schiltz","doi":"10.1021/acs.jmedchem.5c00026","DOIUrl":"10.1021/acs.jmedchem.5c00026","url":null,"abstract":"Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive protein that inhibits antitumor immunity through both tryptophan metabolism and nonenzymatic functions. Drugs targeting IDO1 enzyme activity have failed to improve the overall survival of patients with cancer. Developing new therapeutics that neutralize both enzyme- and nonenzyme-derived immunosuppressive IDO1 effects is therefore of high interest. We previously described a novel proteolysis targeting chimera (PROTAC), NU223612, that degrades IDO1 in cultured human glioblastoma (GBM) cells, as well as in well-established brain tumors, in vivo. In this study, we rationally optimized the structure of our lead series to create NU227326, which degrades IDO1 with a DC50 of 5 nM in human GBM cells. Mechanistic studies showed that IDO1 degradation occurred through the ubiquitin-proteasome system and was sustained for at least 2 days, supporting NU227326 as a highly potent IDO1 PROTAC suitable for further studies in GBM and other human cancers.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412368","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

Lactoferrin Nanoparticle-Vanadium Complex: A Promising High-Efficiency Agent against Glioblastoma by Triggering Autophagy and Ferroptosis

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-02-13 DOI: 10.1021/acs.jmedchem.4c02696

Shuangshuang Gai, Qiwei Yan, Shan Li, Xuwei Zhong, Yiming Qin, Ming Jiang

引用次数: 0

Correction to "Discovery, Synthesis, and Evaluation of Novel Dual Inhibitors of a Vascular Endothelial Growth Factor Receptor and Poly(ADP-Ribose) Polymerase for BRCA Wild-Type Breast Cancer Therapy".

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-02-13 Epub Date: 2025-01-31 DOI: 10.1021/acs.jmedchem.5c00227

Yang Li, Yun Liu, Dan Zhang, Juncheng Chen, Gaoxia Yang, Pan Tang, Chengcan Yang, Jie Liu, Jifa Zhang, Liang Ouyang

引用次数: 0