Journal of Medicinal Chemistry最新文献_第4页

Optimization of Single Relaxin B-Chain Peptide Leads to the Identification of R2R01, a Potent, Long-Acting RXFP1 Agonist for Cardiovascular and Renal Diseases.

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.4c03085

Sergio Mallart, Raffaele Ingenito, Paola Magotti, Alberto Bresciani, Annalise Di Marco, Simone Esposito, Edith Monteagudo, Fulvia Caretti, Laura Orsatti, Alessia Santoprete, Daniela Roversi, Federica Tucci, Maria Veneziano, Denis Brasseur, Xavier Chénedé, Alain Corbier, Laurence Gauzy-Lazo, Vincent Gervat, Frank Marguet, Claire Minoletti, Olivier Pasquier, Bruno Poirier, Aurélien Azam, Bernard Maillère, Elisabetta Bianchi, Philip Janiak, Olivier Duclos, Stephane Illiano

{"title":"Optimization of Single Relaxin B-Chain Peptide Leads to the Identification of R2R01, a Potent, Long-Acting RXFP1 Agonist for Cardiovascular and Renal Diseases.","authors":"Sergio Mallart, Raffaele Ingenito, Paola Magotti, Alberto Bresciani, Annalise Di Marco, Simone Esposito, Edith Monteagudo, Fulvia Caretti, Laura Orsatti, Alessia Santoprete, Daniela Roversi, Federica Tucci, Maria Veneziano, Denis Brasseur, Xavier Chénedé, Alain Corbier, Laurence Gauzy-Lazo, Vincent Gervat, Frank Marguet, Claire Minoletti, Olivier Pasquier, Bruno Poirier, Aurélien Azam, Bernard Maillère, Elisabetta Bianchi, Philip Janiak, Olivier Duclos, Stephane Illiano","doi":"10.1021/acs.jmedchem.4c03085","DOIUrl":"10.1021/acs.jmedchem.4c03085","url":null,"abstract":"Peptide 1, a C18 fatty acid-modified single-chain relaxin analogue, was recently identified as a potent, selective, and long-lasting relaxin family peptide receptor 1 (RXFP1) agonist. Further advanced pharmacokinetic profiling of this compound highlighted elevated levels of oxidative metabolism occurring in dogs and mini pigs but only marginally in rats. This study aimed to design long-lasting relaxin analogues with increased stability against metabolic oxidation while securing subnanomolar RXFP1 potency. Key structural elements, including fatty acid chain length, attachment position, and linker structure, were modified to reduce oxidative metabolism and improve pharmacokinetic parameters. Additionally, incorporating α-methyl lysine (Mly) at position 30, alongside other selective sequence mutations, resulted in several analogues with subnanomolar RXFP1 potency and improved duration of action compared to 1. Compound 21 (R2R01) was then selected as a candidate for an in-depth characterization. It is currently undergoing phase 2 clinical development for renal and cardiovascular diseases.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":"3873-3885"},"PeriodicalIF":6.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062294","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, Synthesis, and Biological Evaluation of Novel Orally Available Covalent CDK12/13 Dual Inhibitors for the Treatment of Tumors. 用于治疗肿瘤的新型口服共价 CDK12/13 双抑制剂的设计、合成和生物学评估。

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-02-13 DOI: 10.1021/acs.jmedchem.4c01616

Hongfu Lu, Deheng Sun, Zhen Wang, Hui Cui, Lihua Min, Haoyu Zhang, Yihong Zhang, Jianping Wu, Xin Cai, Xiao Ding, Man Zhang, Alex Aliper, Feng Ren, Alex Zhavoronkov

引用次数: 0

Exploring the Ascorbate Requirement of the 2-Oxoglutarate-Dependent Dioxygenases.

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.4c02342

Carlos C Smith-Díaz, Andrew B Das, Tomasz P Jurkowski, Timothy A Hore, Margreet C M Vissers

{"title":"Exploring the Ascorbate Requirement of the 2-Oxoglutarate-Dependent Dioxygenases.","authors":"Carlos C Smith-Díaz, Andrew B Das, Tomasz P Jurkowski, Timothy A Hore, Margreet C M Vissers","doi":"10.1021/acs.jmedchem.4c02342","DOIUrl":"10.1021/acs.jmedchem.4c02342","url":null,"abstract":"In humans, the 2-oxoglutarate-dependent dioxygenases (2-OGDDs) catalyze hydroxylation reactions involved in cell metabolism, the biosynthesis of small molecules, DNA and RNA demethylation, the hypoxic response and the formation of collagen. The reaction is catalyzed by a highly oxidizing ferryl-oxo species produced when the active site non-heme iron engages molecular oxygen. Enzyme activity is specifically stimulated by l-ascorbic acid (ascorbate, vitamin C), an effect not well mimicked by other reducing agents. In this perspective article we discuss the reliance of the 2-OGDDs on ascorbate availability. We draw upon findings from studies with different 2-OGDDs to piece together a comprehensive theory for the specific role of ascorbate in supporting enzyme activity. Our discussion centers on the capacity for ascorbate to act as an efficient radical scavenger and its propensity to reduce and chelate transition metals. In addition, we consider the evidence supporting stereospecific binding of ascorbate in the enzyme active site.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":"2219-2237"},"PeriodicalIF":6.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

BRF110, an Orally Active Nurr1-RXRα-Selective Rexinoid, Enhances BDNF Expression without Elevating Triglycerides

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-02-13 DOI: 10.1021/acs.jmedchem.4c03046

Xenophon Asvos, Mohamed A. El Mubarak, Theodoros Karampelas, Theodoros Rampias, Constantin Tamvakopoulos, Gregory B. Sivolapenko, Athanasios Papakyriakou, Stavros Topouzis, Demetrios K. Vassilatis, Demosthenes Fokas

{"title":"BRF110, an Orally Active Nurr1-RXRα-Selective Rexinoid, Enhances BDNF Expression without Elevating Triglycerides","authors":"Xenophon Asvos, Mohamed A. El Mubarak, Theodoros Karampelas, Theodoros Rampias, Constantin Tamvakopoulos, Gregory B. Sivolapenko, Athanasios Papakyriakou, Stavros Topouzis, Demetrios K. Vassilatis, Demosthenes Fokas","doi":"10.1021/acs.jmedchem.4c03046","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03046","url":null,"abstract":"We report the discovery of a Nurr1-RXRα heterodimer-selective rexinoid which emerged from the structural modification of aminopyrimidine XCT0135908. Although XCT0135908 demonstrated high selectivity for the Nurr1-RXRα heterodimer over other RXRα dimerization partners, its poor in vivo stability and limited brain penetration hindered its utility. Structure–activity relationship (SAR) studies alongside bioactivity evaluations of a diverse series of substituted pyrimidines led to BRF110, a brain-penetrant compound retaining the selective activation of the Nurr1-RXRα heterodimer. BRF110, as XCT0135908, protects dopaminergic cells against the Parkinson’s disease-related toxin MPP+ and increases BDNF transcription in mice. Notably, BRF110, in contrast to the market-approved pan-RXR agonist bexarotene, did not elevate triglyceride levels, indicating that enhanced heterodimer selectivity can mitigate off-target in vivo side effects of rexinoids. These findings highlight the potential of heterodimer-selective scaffolds as a strategy for improving the therapeutic profile of rexinoids, addressing significant challenges in the clinical development of RXR-targeting molecules.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"63 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401882","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

Imaging CDK4/6 Broaden Options of Breast Cancer Diagnostics with Positron Emission Tomography

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-02-13 DOI: 10.1021/acs.jmedchem.4c02672

Mengjing Ji, Xiangwei Wang, Cheng Liu, Guang Ma, Xin Lu, Bin Zhu, Simin He, Jianping Zhang, Xiaoping Xu, Shaoli Song, Zhongyi Yang

{"title":"Imaging CDK4/6 Broaden Options of Breast Cancer Diagnostics with Positron Emission Tomography","authors":"Mengjing Ji, Xiangwei Wang, Cheng Liu, Guang Ma, Xin Lu, Bin Zhu, Simin He, Jianping Zhang, Xiaoping Xu, Shaoli Song, Zhongyi Yang","doi":"10.1021/acs.jmedchem.4c02672","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02672","url":null,"abstract":"This study developed a novel PET radiotracer to screen breast cancer patients sensitive to CDK4/6 inhibitors, guiding personalized treatment. Two CDK4/6-targeting precursors were synthesized and evaluated in vitro and in vivo. Three breast cancer cell lines─MCF-7, MDA-MB-231, and MDA-MB-468─were selected based on decreasing sensitivity to palbociclib. Compared to [68Ga]Ga-DOTA-Hexa-CDKi, [68Ga]Ga-DOTA-Bua-CDKi clearly identified cell lines with high sensitivity to palbociclib. PET/CT imaging showed significantly higher uptake of [68Ga]Ga-DOTA-Bua-CDKi (8.40 ± 0.85%ID/g) in MCF-7 tumors 60 min after tracer injection, with significant differences in tumor uptake among the three models (P < 0.05). Blocking assays demonstrated specific tumor uptake of [68Ga]Ga-DOTA-Bua-CDKi. Biosafety tests validated its safety as a diagnostic agent. [68Ga]Ga-DOTA-Bua-CDKi showed highly specific targeting of CDK4/6 and effective contrast imaging in tumor models. To our knowledge, [68Ga]Ga-DOTA-Bua-CDKi is one of the first radiotracers to assess CDK inhibitor sensitivity, offering promise for evaluating patient responses to CDK4/6 inhibitors.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"28 2 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401907","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

Elucidation of Postfusion Structures of the Measles Virus F Protein for the Structure-Based Design of Fusion Inhibitors.

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.4c02337

Aoi Takahara, Toru Nakatsu, Kazushige Hirata, Hironori Hayashi, Kumi Kawaji, Keisuke Aoki, Shinsuke Inuki, Hiroaki Ohno, Hiroaki Kato, Eiichi Kodama, Shinya Oishi

{"title":"Elucidation of Postfusion Structures of the Measles Virus F Protein for the Structure-Based Design of Fusion Inhibitors.","authors":"Aoi Takahara, Toru Nakatsu, Kazushige Hirata, Hironori Hayashi, Kumi Kawaji, Keisuke Aoki, Shinsuke Inuki, Hiroaki Ohno, Hiroaki Kato, Eiichi Kodama, Shinya Oishi","doi":"10.1021/acs.jmedchem.4c02337","DOIUrl":"10.1021/acs.jmedchem.4c02337","url":null,"abstract":"Measles is a highly infectious disease and remains a major cause of childhood mortality worldwide. In some cases, the measles virus (MV) induces subacute sclerosing panencephalitis within several years of the acute infection. The infection of the target cells by MV is mediated by the F protein, in which two heptad repeat regions, HR1 and HR2, form a six-helix bundle before membrane fusion. We previously reported anti-MV peptides, which were designed from the HR region of the MV F protein. Here, we characterized the essential interactions between the HR1 and HR2 regions on the postfusion six-helix bundles of synthetic HR1 and HR2 peptides by crystallographic studies. Based on the crystal structures, we identified the minimal α-helix sequence for antiviral activity. Additionally, optimizing HR2 peptides by introducing α-helix-inducible motifs and maintaining key hydrogen bond networks at the N- and C-terminal regions led to the identification of highly potent antiviral peptides.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":"3123-3133"},"PeriodicalIF":6.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062252","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

Exploring Alternative Zinc-Binding Groups in Histone Deacetylase (HDAC) Inhibitors Uncovers DS-103 as a Potent Ethylhydrazide-Based HDAC Inhibitor with Chemosensitizing Properties.

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-02-13 DOI: 10.1021/acs.jmedchem.4c02373

Daniel Stopper, Lukas Biermann, Paris R Watson, Jingyu Li, Beate König, Matthew N Gaynes, Lais Pessanha de Carvalho, Jana Klose, Maria Hanl, Alexandra Hamacher, Linda Schäker-Hübner, Daniel Ramsbeck, Jana Held, David W Christianson, Matthias U Kassack, Finn K Hansen

{"title":"Exploring Alternative Zinc-Binding Groups in Histone Deacetylase (HDAC) Inhibitors Uncovers DS-103 as a Potent Ethylhydrazide-Based HDAC Inhibitor with Chemosensitizing Properties.","authors":"Daniel Stopper, Lukas Biermann, Paris R Watson, Jingyu Li, Beate König, Matthew N Gaynes, Lais Pessanha de Carvalho, Jana Klose, Maria Hanl, Alexandra Hamacher, Linda Schäker-Hübner, Daniel Ramsbeck, Jana Held, David W Christianson, Matthias U Kassack, Finn K Hansen","doi":"10.1021/acs.jmedchem.4c02373","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02373","url":null,"abstract":"In this work, we synthesized a series of peptoid-based histone deacetylase (HDAC) inhibitors with variations in the linker region and zinc-binding groups. All compounds were investigated for their HDAC inhibition, antiplasmodial activity, and cytotoxicity against native and cisplatin-resistant carcinoma cell lines. The ethylhydrazide 20 (DS-103) proved to be the most effective compound in these primary screenings. DS-103 showed nanomolar inhibition of class I HDACs and of HDAC6 (class IIb). To further investigate the binding mode of DS-103, a crystal structure of DS-103 in complex with HDAC6 was obtained, which represents the first reported crystal structure of an alkylhydrazide in complex with an HDAC enzyme. Importantly, DS-103 completely reversed cisplatin resistance in two different platinum-resistant solid cancer cell lines and demonstrated strong synergism with cisplatin. The synergistic anticancer effects are mediated by increased DNA damage and p21 expression, resulting in caspase-mediated apoptosis and cell death.","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":"143412367","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

Octa-Cationic Porphyrin-Functionalized Biocompatible Nanocomposite: A Promising Candidate for Enhanced Combinatorial Photodynamic and Photothermal Tumor Therapy.

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-02-13 Epub Date: 2025-01-26 DOI: 10.1021/acs.jmedchem.4c02584

Chang-Hao Jiang, Yong-Hui Li, Yue Yuan, Chen-Yu Wang, Jun-Qing Chu, Gui-Mei Han, De-Ming Kong, Qi-Liang Cai, Li-Na Zhu

{"title":"Octa-Cationic Porphyrin-Functionalized Biocompatible Nanocomposite: A Promising Candidate for Enhanced Combinatorial Photodynamic and Photothermal Tumor Therapy.","authors":"Chang-Hao Jiang, Yong-Hui Li, Yue Yuan, Chen-Yu Wang, Jun-Qing Chu, Gui-Mei Han, De-Ming Kong, Qi-Liang Cai, Li-Na Zhu","doi":"10.1021/acs.jmedchem.4c02584","DOIUrl":"10.1021/acs.jmedchem.4c02584","url":null,"abstract":"The integration of photodynamic therapy (PDT) and photothermal therapy (PTT) offers a promising strategy for enhancing phototherapy efficiency. Herein, we present a dual-functional, biocompatible nanocomposite system for combination PDT/PTT therapy. The system utilizes a highly biocompatible nanoparticle assembled by an amphiphilic short peptide with the assistance of Zn2+ as a carrier. The photothermal convertor is loaded within the nanoparticle, while a cationic porphyrin photosensitizer is assembled on the surface. The water-soluble cationic porphyrin (M8PzEOPP), designed with eight positive charges, provides a strong electrostatic interaction for stable assembly on the nanocomposite surface. This location-independent assembly effectively maintains the optical characteristics of both the photosensitizer and the photothermal convertor, endowing the nanocomposite with effective photodynamic and photothermal properties. The nanocomposite exhibits excellent tumor-targeting accumulation behavior, low dark toxicity, robust extracellular biostability, and high cell internalization efficiency. Its enhanced performance in combinatorial therapy is demonstrated through both in vitro and in vivo experiments.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":"3409-3419"},"PeriodicalIF":6.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044973","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

Development of a Highly Selective Ferroptosis Inducer Targeting GPX4 with 2-Ethynylthiazole-4-carboxamide as Electrophilic Warhead.

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.4c02530

Sunkai Gu, Guanyu Yang, Hongyuan Bian, Fan Yang, Yajing Zhang, Yanhong Huang, Rui Su, Huilian Zhang, Xiuchun Zhao, Jin Liu, Shuheng Huang, Ling Huang, Benxin Hou, Yong Rao, Congjun Xu

{"title":"Development of a Highly Selective Ferroptosis Inducer Targeting GPX4 with 2-Ethynylthiazole-4-carboxamide as Electrophilic Warhead.","authors":"Sunkai Gu, Guanyu Yang, Hongyuan Bian, Fan Yang, Yajing Zhang, Yanhong Huang, Rui Su, Huilian Zhang, Xiuchun Zhao, Jin Liu, Shuheng Huang, Ling Huang, Benxin Hou, Yong Rao, Congjun Xu","doi":"10.1021/acs.jmedchem.4c02530","DOIUrl":"10.1021/acs.jmedchem.4c02530","url":null,"abstract":"A highly selective ferroptosis inducer with drug-like properties can significantly advance the research on inducing ferroptosis for anticancer treatment. We previously reported a highly active GPX4 inhibitor 26a, but its activity and stability need further improvement. In this work, a novel GPX4 inhibitor (R)-9i with more potent cytotoxicity (IC50 = 0.0003 μM against HT1080) and ferroptosis selectivity (selectivity index = 24933) was gained via further electrophilic warhead screening and structure-based optimization. The cellular thermal shift assay (CETSA) indicated that (R)-9i could stabilize GPX4 with a Tm value of 6.2 °C. Furthermore, (R)-9i showed strong binding affinity against GPX4 (KD = 20.4 nM). More importantly, (R)-9i has more favorable pharmacokinetic properties than 26a, which endowed (R)-9i with potential in antitumor research and as a tool drug for further study of ferroptosis. Associated with these, (R)-9i treatment significantly inhibited tumor growth in the xenograft tumor mouse model without detectable toxicity.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":"3309-3323"},"PeriodicalIF":6.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062213","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 of a Potent, Selective, and Metabolically Stable CDK9 Inhibitor to Counteract Osimertinib Resistance through Mcl-1 Suppression and Enhanced BRD4 Co-Targeting.

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-02-13 DOI: 10.1021/acs.jmedchem.4c03168

Tizhi Wu, Jiali Huang, Xiankang Zhang, Feihai Ma, Shijing Yu, Yifang Liu, Yifan Xu, Shiqi Wu, Alexander V Finko, Zhiyu Li, Li Feng, Jinlei Bian

{"title":"Rational Design of a Potent, Selective, and Metabolically Stable CDK9 Inhibitor to Counteract Osimertinib Resistance through Mcl-1 Suppression and Enhanced BRD4 Co-Targeting.","authors":"Tizhi Wu, Jiali Huang, Xiankang Zhang, Feihai Ma, Shijing Yu, Yifang Liu, Yifan Xu, Shiqi Wu, Alexander V Finko, Zhiyu Li, Li Feng, Jinlei Bian","doi":"10.1021/acs.jmedchem.4c03168","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03168","url":null,"abstract":"Overcoming osimertinib resistance in NSCLC treatment remains a significant clinical challenge. CDK9 has emerged as a promising target due to its critical role in sustaining oncogenic transcriptional programs, particularly via Mcl-1 regulation. Herein, we report the structure-guided optimization of a previously identified CDK9 inhibitor (Z11), resulting in the discovery of T7, a potent, selective, and metabolically stable candidate (IC50 = 1.2 nM). T7 effectively suppressed cell proliferation, reduced colony formation, and induced apoptosis in Osimertinib-resistant NSCLC cells by downregulating Mcl-1. Furthermore, T7 significantly inhibited the growth of resistant organoids and demonstrated marked antitumor efficacy in a xenograft model. Notably, combining T7 with the BRD4 inhibitor JQ1 further enhanced antitumor activity both in vitro and in vivo, revealing a complementary therapeutic strategy. These findings identify T7 as a promising next-generation CDK9 inhibitor for addressing Osimertinib resistance in NSCLC and underscore the potential of transcriptional cotargeting approaches to improve clinical outcomes.","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":"143412369","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