European Journal of Medicinal Chemistry最新文献_第6页

Discovery of new fungal jumonji H3K27 demethylase inhibitors for the treatment of Cryptococcus neoformans and Candida auris infections 发现治疗新生隐球菌和白色念珠菌感染的新型真菌 Jumonji H3K27 去甲基化酶抑制剂

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-11-06 DOI: 10.1016/j.ejmech.2024.117028

Xin Liu , Wang Li , Yang Liu , Xiaoqing Wang , Qiao Shi , Wanzhen Yang , Jie Tu , Yan Wang , Chunquan Sheng , Na Liu

{"title":"Discovery of new fungal jumonji H3K27 demethylase inhibitors for the treatment of Cryptococcus neoformans and Candida auris infections","authors":"Xin Liu , Wang Li , Yang Liu , Xiaoqing Wang , Qiao Shi , Wanzhen Yang , Jie Tu , Yan Wang , Chunquan Sheng , Na Liu","doi":"10.1016/j.ejmech.2024.117028","DOIUrl":"10.1016/j.ejmech.2024.117028","url":null,"abstract":"<div><div>Invasive fungal infections have become a serious public health problem. To tackle the challenges of limited efficacy in antifungal therapy and severe drug resistance, antifungal drugs with new mechanisms of action are urgently needed. Our previous study identified <strong>JIB-04</strong> to be an inhibitor of fungal histone demethylase (HDM). To promote target validation and inhibitor design, herein a series of new <strong>JIB-04</strong> derivatives were designed and synthesized. After the establishment of structure-activity relationship, compound <strong>A4</strong> was identified to possess potent antifungal activity against <em>Cryptococcus neoformans</em> and <em>Candida auris</em>. Compared to lead compound <strong>JIB-04</strong>, compound <strong>A4</strong> was a more potent HDM inhibitor and exhibited better water solubility, virulence factors inhibitory activity and <em>in vivo</em> antifungal potency. Collectively, this study further confirmed that fungal HDMs were potential antifungal targets and compound <strong>A4</strong> was a promising antifungal lead compound.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117028"},"PeriodicalIF":6.0,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 pyrrolopyrimidinone derivatives as potent PKMYT1 inhibitors for the treatment of cancer 发现吡咯并嘧啶酮衍生物作为治疗癌症的强效 PKMYT1 抑制剂

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-11-05 DOI: 10.1016/j.ejmech.2024.117025

Chao Wang , Yazhou Wang , Fanye Meng , Tingting Liu , Xiaomin Wang , Xin Cai , Man Zhang , Alex Aliper , Feng Ren , Alex Zhavoronkov , Xiao Ding

{"title":"Discovery of pyrrolopyrimidinone derivatives as potent PKMYT1 inhibitors for the treatment of cancer","authors":"Chao Wang , Yazhou Wang , Fanye Meng , Tingting Liu , Xiaomin Wang , Xin Cai , Man Zhang , Alex Aliper , Feng Ren , Alex Zhavoronkov , Xiao Ding","doi":"10.1016/j.ejmech.2024.117025","DOIUrl":"10.1016/j.ejmech.2024.117025","url":null,"abstract":"<div><div>The protein kinase PKMYT1 is responsible for inhibitory CDK1 phosphorylation, thus playing a central role in regulating the G2/M cell cycle checkpoint. As many cancers have dysfunctional cell cycle checkpoint signaling, PKMYT1 inhibition is emerging as an attractive target in advanced tumors. PKMYT1 inhibitors, however, have encountered difficulties in balancing biological efficacy, on-target specificity, and favorable stability and other drug-like properties. Herein, we report the design and development of pyrrolopyrimidinone derivatives intended to simultaneously restrict molecular conformation and shield a metabolic site in order to optimize stability. Compound <strong>7</strong> demonstrated strong PKMYT1-specific inhibition, a subsequent decrease in CDK1 phosphorylation, and antitumor efficacy <em>in vitro</em>, as well as enhanced metabolic stability, favorable pharmacokinetic and bioavailability properties, and potent antitumor <em>in vivo</em> efficacy. Our findings indicate that compound <strong>7</strong> is a promising PKMYT1 inhibitor for the treatment of advanced cancers with cell cycle defects.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117025"},"PeriodicalIF":6.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 cytotoxicity screening of novel pyrazolopyrimidines over renal cell carcinoma (UO-31 cells) as p38α inhibitors, and apoptotic cells inducing activities 新型吡唑并嘧啶作为 p38α 抑制剂和细胞凋亡诱导剂对肾细胞癌（UO-31 细胞）的设计、合成和细胞毒性筛选

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-11-05 DOI: 10.1016/j.ejmech.2024.117005

Sara Y. Ewieda , Amr Sonousi , Aliaa M. Kamal , Mohamed K. Abdelhamid

{"title":"Design, synthesis, and cytotoxicity screening of novel pyrazolopyrimidines over renal cell carcinoma (UO-31 cells) as p38α inhibitors, and apoptotic cells inducing activities","authors":"Sara Y. Ewieda , Amr Sonousi , Aliaa M. Kamal , Mohamed K. Abdelhamid","doi":"10.1016/j.ejmech.2024.117005","DOIUrl":"10.1016/j.ejmech.2024.117005","url":null,"abstract":"<div><div>A series of novel molecules with pyrazolopyrimidine-4-amine core were designed and synthesized as potential cytotoxic agents over Renal Cell Carcinoma cells (UO-31). Results of cytotoxic activity against UO-31 cells showed that pyrazolopyrimidines <strong>19</strong> and <strong>31</strong> were found to be more cytotoxic than sorafenib (SOR). The cytotoxic activity of these compounds appeared to correlate with their ability to inhibit p38α MAPK which are 2.53- and 2.27- folds more potent than SOR. Moreover, results of the cell cycle analysis as well as the results of annexin-V on the (UO-31) cells showed that pyrazolopyrimidines <strong>19</strong> and <strong>31</strong> had a pro-apoptotic activity higher than SOR by 1.42- and 1.20- folds, respectively. Furthermore, compounds <strong>19</strong> and <strong>31</strong> were found to be effective in arresting the cell cycle throughout the accumulation of the cells at G2/M phase. Finally, the tested compounds decreased the TNF concentration as well as increased the expression of tumor suppressor gene p53, Bax/BCL-2 ratio and caspase 3/7.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117005"},"PeriodicalIF":6.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142588325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 cloxiquine derivatives as potent HDAC inhibitors for the treatment of melanoma via activating PPARγ 发现通过激活 PPARγ 治疗黑色素瘤的强效 HDAC 抑制剂氯喹衍生物

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-11-04 DOI: 10.1016/j.ejmech.2024.117029

Limin Yang , Ran Ding , Xiaojie Tong , Tong Shen , Shuting Jia , Xiqing Yan , Chong Zhang , Liqiang Wu

{"title":"Discovery of cloxiquine derivatives as potent HDAC inhibitors for the treatment of melanoma via activating PPARγ","authors":"Limin Yang , Ran Ding , Xiaojie Tong , Tong Shen , Shuting Jia , Xiqing Yan , Chong Zhang , Liqiang Wu","doi":"10.1016/j.ejmech.2024.117029","DOIUrl":"10.1016/j.ejmech.2024.117029","url":null,"abstract":"<div><div>The combined treatment with histone deacetylase (HDAC) inhibitors with peroxisome proliferator-activated receptor γ (PPARγ) agonists has displayed significant anticancer efficacy. Based on these results, a series of cloxiquine derivatives were prepared as potent HDAC inhibitors for the treatment of melanoma. Among these compounds, <strong>CS4</strong> exhibited excellent inhibitory effects on HDAC1 (IC<sub>50</sub> = 38 nM) and HDAC6 (IC<sub>50</sub> = 12 nM), and had good antiproliferative effects against A375 and SK-MEL-5 melanoma cells (IC<sub>50</sub> values, 1.20 and 0.93 μM, respectively). Mechanism research indicated that <strong>CS4</strong> inhibited SK-MEL-5 cell growth by promoting α-tubulin and histone 3 (H3) acetylation. At the metabolic level, treatment with <strong>BG11</strong> activated PPARγ and blocked glycolysis in SK-MEL-5 cells, which mediated partial antimelanoma effects of <strong>CS4</strong>. In addition, <strong>CS4</strong> also induced cell cycle arrest at G2, suppressed migration and facilitated apoptosis of SK-MEL-5 cells. More importantly, compound <strong>CS4</strong> demonstrated significant <em>in vivo</em> anticancer effect compared with SAHA, and exhibited neglectable toxicity. Consequently, <strong>CS4</strong> is the potent HDAC inhibitor, which may be developed as the candidate antimelanoma drug.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117029"},"PeriodicalIF":6.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 hybrid aptamers-engineered PROTACs for degrading VEGF165 in both tumor- and vascular endothelial cells 开发可在肿瘤细胞和血管内皮细胞中降解 VEGF165 的混合适配体工程化 PROTACs

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-11-02 DOI: 10.1016/j.ejmech.2024.117027

Ziting Feng , Duoli Xie , Fang Qiu , Jie Huang , Zhuqian Wang , Chao Liang

{"title":"Development of hybrid aptamers-engineered PROTACs for degrading VEGF165 in both tumor- and vascular endothelial cells","authors":"Ziting Feng , Duoli Xie , Fang Qiu , Jie Huang , Zhuqian Wang , Chao Liang","doi":"10.1016/j.ejmech.2024.117027","DOIUrl":"10.1016/j.ejmech.2024.117027","url":null,"abstract":"<div><div>Tumors and angiogenesis are connected through a complex interplay. VEGF165, generated from both tumor and vascular endothelial cells, serves as a mutual benefit for both cell types. Therapeutic approaches modulating VEGF165 have been proposed as promising antitumor therapies. PROTACs are bifunctional molecules that exploit the intracellular ubiquitin-proteasome system to degrade specific proteins. To date, there are no targeted PROTACs designed to degrade VEGF165 in both tumor and vascular endothelial cells. The aptamer AS1411 is notable for its ability to selectively recognize and enter both tumor and vascular endothelial cells by targeting the cell surface nucleolin (NCL). Moreover, AS1411 has also been repurposed as an intracellular recruiter of E3 ligase MDM2 via leveraging NCL as a molecular bridge. In this study, we conjugated AS1411 with a VEGF165-specific aptamer V7t1, creating hybrid aptamers-engineered PROTACs. The PROTACs demonstrate remarkable selectivity for both tumor and vascular endothelial cells and facilitate the ubiquitination and proteasomal degradation of VEGF165. The PROTACs inhibit the growth of tumor cells and also impede angiogenesis, without causing toxicity to normal tissues. The hybrid aptamers-engineered PROTACs provide an avenue for disrupting the tumor-angiogenesis interplay through modulation of VEGF165 in both tumor and vascular endothelial cells.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117027"},"PeriodicalIF":6.0,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Recent report on indoles as a privileged anti-viral scaffold in drug discovery 关于吲哚作为药物研发中的抗病毒支架的最新报告

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-11-01 DOI: 10.1016/j.ejmech.2024.117017

Asmita Singh , Charu Bhutani , Pankaj Khanna , Sangeeta Talwar , Sandeep Kumar Singh , Leena Khanna

{"title":"Recent report on indoles as a privileged anti-viral scaffold in drug discovery","authors":"Asmita Singh , Charu Bhutani , Pankaj Khanna , Sangeeta Talwar , Sandeep Kumar Singh , Leena Khanna","doi":"10.1016/j.ejmech.2024.117017","DOIUrl":"10.1016/j.ejmech.2024.117017","url":null,"abstract":"<div><div>In recent years, viral infections such as COVID-19, Zika virus, Nipah virus, Ebola, Influenza, Monkeypox, and Dengue have substantially impacted global health. These outbreaks have led to heightened global health initiatives and collaborative efforts to address and mitigate these significant threats effectively. Thus, developing antiviral treatments and research in this field has become highly important. Heterocycles, particularly indole motifs, have been a valuable resource in drug discovery, as they can be used as treatments or inspire the synthesis of new potent candidates. Indole-containing drugs, such as enfuvirtide (T-20), arbidol, and delavirdine, have demonstrated significant efficacy in treating viral diseases. This review aims to comprehensively assess the latest research and developments in novel indoles as potential scaffolds for antiviral activity. We have compiled detailed information about indoles as potential antivirals by conducting a thorough literature survey from the past ten years. The review includes discussions on synthetic protocols, inhibitory concentrations, SAR study, and computational study. This review shall identify new antiviral indoles that may help to combat new viral threats in the future.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117017"},"PeriodicalIF":6.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Tubulin/HDAC dual-target inhibitors: Insights from design strategies, SARs, and therapeutic potential 微管蛋白/HDAC 双靶点抑制剂：从设计策略、SARs 和治疗潜力中获得的启示

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-11-01 DOI: 10.1016/j.ejmech.2024.117022

Zhen Zhang , Rui Su , Junao Liu , Keyu Chen , Chengjun Wu , Pinghua Sun , Tiemin Sun

{"title":"Tubulin/HDAC dual-target inhibitors: Insights from design strategies, SARs, and therapeutic potential","authors":"Zhen Zhang , Rui Su , Junao Liu , Keyu Chen , Chengjun Wu , Pinghua Sun , Tiemin Sun","doi":"10.1016/j.ejmech.2024.117022","DOIUrl":"10.1016/j.ejmech.2024.117022","url":null,"abstract":"<div><div>Microtubules, one of the cytoskeletons in eukaryotic cells, maintain the proper operation of several cellular functions. Additionally, they are regulated by the acetylation of HDAC6 and SIRT2 which affects microtubule dynamics. Given the fact that tubulin and HDAC inhibitors play a synergistic effect in the treatment of many cancers, the development of tubulin/HDAC dual-target inhibitors is conducive to addressing multiple limitations including drug resistance, dose toxicity, and unpredictable pharmacokinetic properties. At present, tubulin/HDAC dual-target inhibitors have been obtained in three main ways: uncleavable linked pharmacophores, cleavable linked pharmacophores, and modification of single-target drugs. Their therapeutic efficacy has been verified in <em>vivo</em> and in <em>vitro</em> assays. In this article, we reviewed the research progress of tubulin/HDAC dual inhibitors from design strategies, SARs, and biological activities, which may provide help for the discovery of novel tubulin/HDAC dual inhibitors.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117022"},"PeriodicalIF":6.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Advance on the effects of algal carotenoids on inflammatory signaling pathways 藻类类胡萝卜素对炎症信号通路影响的研究进展

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-11-01 DOI: 10.1016/j.ejmech.2024.117020

Yudi Wang , Xinrong Geng , Song Qin , Tuanjie Che , Libo Yan , Biao Yuan , Wenjun Li

{"title":"Advance on the effects of algal carotenoids on inflammatory signaling pathways","authors":"Yudi Wang , Xinrong Geng , Song Qin , Tuanjie Che , Libo Yan , Biao Yuan , Wenjun Li","doi":"10.1016/j.ejmech.2024.117020","DOIUrl":"10.1016/j.ejmech.2024.117020","url":null,"abstract":"<div><div>The development of inflammation has an indispensable importance in the self-protection of the human body. However, over-inflammation may damage human health, and inflammatory pathways and inflammasomes have a significant impact on the onset of inflammation. Therefore, how to constrain the development of inflammation through inflammatory pathways or inflammasomes becomes a hot research issue. Carotenoids are a natural pigment and an active substance in algae, with anti-inflammatory and antioxidant effects. Many studies have shown that carotenoids have inhibitory effects on the inflammatory pathways and inflammasomes. In this review, we discussed the mechanism of carotenoids targeting those important inflammatory pathways and their effects on common inflammasome NLRP3 and inflammation-related diseases from the perspective of several inflammatory pathways, including p38 MAPK, IL-6/JAK/STAT3, and PI3K, with a focus on the targets and targeting effects of carotenoids on different inflammatory signaling pathways, and at last proposed possible anti-inflammatory targets.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117020"},"PeriodicalIF":6.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 evaluation of 4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine derivatives as potential glutaminyl cyclase isoenzyme inhibitors for the treatment of cancer 设计、合成和评估 4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶衍生物作为治疗癌症的潜在谷氨酰胺环化酶同工酶抑制剂

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-11-01 DOI: 10.1016/j.ejmech.2024.117019

Qingqing Zhou , Zhenxin Wu , Feixia Qin , Pan He , Zhuoran Wang , Fangyi Zhu , Ying Gao , Wei Xiong , Chenyang Li , Haiqiang Wu

{"title":"Design, synthesis, and evaluation of 4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine derivatives as potential glutaminyl cyclase isoenzyme inhibitors for the treatment of cancer","authors":"Qingqing Zhou , Zhenxin Wu , Feixia Qin , Pan He , Zhuoran Wang , Fangyi Zhu , Ying Gao , Wei Xiong , Chenyang Li , Haiqiang Wu","doi":"10.1016/j.ejmech.2024.117019","DOIUrl":"10.1016/j.ejmech.2024.117019","url":null,"abstract":"<div><div>Upregulated glutaminyl cyclase isoenzyme (isoQC) contributes to cancer development by catalyzing pE-CD47 generation and thus enhancing CD47-SIRPα binding and subsequent “don't eat me” signals. We thus consider that isoQC could represent a novel target for cancer therapy. We previously prepared a series of diphenyl conjugated imidazole derivatives (DPCIs) and evaluated their use as glutaminyl cyclase (QC) inhibitors. Here, a new series of DPCIs was rationally designed and synthesized. As anticipated, the analogues exhibited considerably improved inhibitory potency against both QC and isoQC. Crucially, these chemicals exhibited marked selectivity toward isoQC. Further assessments established that one selected compound (<strong>27</strong>) did not affect the viability of A549, H1299, PC9, or HEK293T cells or the body weight of mice. This compound did, however, reduce pE-CD47 levels in infected A549 cells (isoQC_OE and isoQC_KD) and exhibited apparent anti-cancer effects <em>in vivo</em> by downregulating the level of pE-CD47 via the inhibition of isoQC activity. Taken together, these findings indicated that the compounds synthesized in this study could represent potential QC/isoQC inhibitors for the treatment of cancers.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117019"},"PeriodicalIF":6.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 the first selective and potent PROTAC degrader for the pseudokinase TRIB2 发现首个针对伪激酶 TRIB2 的选择性强效 PROTAC 降解剂

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2024-11-01 DOI: 10.1016/j.ejmech.2024.117016

Chaowei Wen , Prathibha R. Gajjala , Yihan Liu , Bingzhong Chen , Mehtab S. Bal , Payal Sutaria , Qiao Yuanyuan , Yang Zheng , Yang Zhou , Jinwei Zhang , Weixue Huang , Xiaomei Ren , Zhen Wang , Ke Ding , Arul M. Chinnaiyan , Fengtao Zhou

{"title":"Discovery of the first selective and potent PROTAC degrader for the pseudokinase TRIB2","authors":"Chaowei Wen , Prathibha R. Gajjala , Yihan Liu , Bingzhong Chen , Mehtab S. Bal , Payal Sutaria , Qiao Yuanyuan , Yang Zheng , Yang Zhou , Jinwei Zhang , Weixue Huang , Xiaomei Ren , Zhen Wang , Ke Ding , Arul M. Chinnaiyan , Fengtao Zhou","doi":"10.1016/j.ejmech.2024.117016","DOIUrl":"10.1016/j.ejmech.2024.117016","url":null,"abstract":"<div><div>Pseudokinase TRIB2, a member of the CAMK Ser/Thr protein kinase family, regulates various cellular processes through phosphorylation-independent mechanisms. Dysregulation of TRIB2 has been implicated in promoting tumor growth, metastasis, and therapy resistance, making it a promising target for cancer treatment. In this study, we designed and synthesized a series of TRIB2 PROTAC degraders by conjugating a TRIB2 binder <strong>1</strong> with VHL or CRBN ligands via linkers of varying lengths and compositions. Among these compounds, <strong>5k</strong> demonstrated potent TRIB2 degradation with a DC<sub>50</sub> value of 16.84 nM (95 % CI: 13.66–20.64 nM) in prostate cancer PC3 cells. Mechanistic studies revealed that <strong>5k</strong> directly interacted with TRIB2, selectively inducing its degradation through a CRBN-dependent ubiquitin-proteasomal pathway. Moreover, <strong>5k</strong> outperformed the TRIB2 binder alone in inhibiting cell proliferation and inducing apoptosis, confirming that TRIB2 protein degradation could be a promising therapeutic strategy for TRIB2-associated cancers. Additionally, compound <strong>5k</strong> also serves as an effective tool for probing TRIB2 biology.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117016"},"PeriodicalIF":6.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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