Bioorganic & Medicinal Chemistry最新文献_第8页

Exploring structure-directed immunogenic cytotoxicity of arginine-rich peptides for cytolysis-induced immunotherapy of cancer 探索富含精氨酸肽的结构定向免疫细胞毒性，用于细胞溶解诱导的癌症免疫疗法。

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-11-08 DOI: 10.1016/j.bmc.2024.117984

Liu Huang , Ang Li , Han-jie Liu , Shuang-shuang Ji , Hao Fei

{"title":"Exploring structure-directed immunogenic cytotoxicity of arginine-rich peptides for cytolysis-induced immunotherapy of cancer","authors":"Liu Huang , Ang Li , Han-jie Liu , Shuang-shuang Ji , Hao Fei","doi":"10.1016/j.bmc.2024.117984","DOIUrl":"10.1016/j.bmc.2024.117984","url":null,"abstract":"<div><div>The same cells can die with varied immunological consequences. For the purpose of cancer therapy, stronger immunogenic death of cancer cells is considered favorable. Membrane disruptive peptides are cytotoxic agents with tunable structures capable of not just killing heterogeneous cancer cells, but also inducing immunogenic death. However, the chemo-structural principles that underlie their immunogenic cytotoxicity remain elusive. Here we investigated a series of arginine-rich amphipathic peptides with representative structures on the relationship between the mode of cell death and the immunogenic potency. Among several hydrophobic motif-appended cyclic octaarginine peptides, FC-14 was found to induce cell stress and necroptotic death, unlike apoptotic peptide RL2 and membrane-dissolving peptide RL1. Their differing abilities to release immunogenic death markers correlated well with their potential to activate innate immunity and protective vaccinal effect in a prophylactic model, with FC-14 being the most potent. FC-14 can be <u>p</u>re-<u>op</u>sonized with <u>a</u>lbumin into <u>n</u>anoparticles (PopAN-FC-14) using PopAN technology to improve its pharmacokinetic properties for intravenous injection. In a syngeneic mouse model of subcutaneous breast cancer, PopAN-FC-14 showed superior therapeutic effect and safety profile than the albumin formulated nanomedicine Nab-paclitaxel (Nab-PTX). Boost injections of PopAN-FC-14 significantly enhanced tumor-specific cellular and humoral immunities, acting similarly as <em>in-situ</em> cancer vaccine. Overall, this work demonstrates a novel focus on the immunogenic cytotoxicity of peptides and a practical approach for effective systemic therapy of cancer.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 117984"},"PeriodicalIF":3.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Sulfonamide-derivatized galactosides selectively target an unexplored binding site in the galectin-9N-terminal domain 磺胺衍生物化半乳糖苷可选择性地靶向galectin-9N-末端结构域中一个尚未探索的结合位点。

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-11-07 DOI: 10.1016/j.bmc.2024.117989

Mukul Mahanti , Sofi Gummesson , Anders Sundin , Hakon Leffler , Fredrik Zetterberg , Ulf J Nilsson

{"title":"Sulfonamide-derivatized galactosides selectively target an unexplored binding site in the galectin-9N-terminal domain","authors":"Mukul Mahanti , Sofi Gummesson , Anders Sundin , Hakon Leffler , Fredrik Zetterberg , Ulf J Nilsson","doi":"10.1016/j.bmc.2024.117989","DOIUrl":"10.1016/j.bmc.2024.117989","url":null,"abstract":"<div><div>Four directional and positional variants of sulfonamide-derivatized galactopyranosides were synthesized and evaluated against human galectin-1, -3, -4C (C-terminal), -7, -8N (N-terminal), -8C (C-terminal), -9N (N-terminal), and -9C (C-terminal), which revealed that one of the sulfonamide positions and directionalities (methyl 3-{4-[2-(phenylsulfonylamino)-phenyl]-triazolyl}-3-deoxy-α-<span>d</span>-galactopyranosides) bound with 6–15 fold higher affinity than the corresponding phenyltriazole (lacking the phenylsulfonamide moiety) for galectin-9N. Molecular dynamic simulations suggested that inhibitor adopted a conformation that is complementary to the galectin-9N binding site and where the sulfonamide moiety protrudes into an unexplored and non-conserved binding site perpendicular to and below the A–B subsite to interact with a His61 N<img>H proton. This resulted in the discovery of galectin-9N inhibitors with unprecedented selectivity over other galectins, thus constituting valuable tools for studies of the biological functions of galectin-9.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 117989"},"PeriodicalIF":3.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Synthesis of α-fluorocinnamate derivatives as novel cathepsin S inhibitors with in vitro antiproliferative activity against pancreatic cancer cells 合成具有体外抗胰腺癌细胞增殖活性的α-氟肉桂酸酯衍生物作为新型胰蛋白酶 S 抑制剂

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-11-05 DOI: 10.1016/j.bmc.2024.117987

Andrea Citarella , Serena Petrella , Davide Moi , Alessandro Dimasi , Tommaso Braga , Lorenzo Ruberto , Stefano Pieraccini , Maurizio Sironi , Nicola Micale , Tanja Schirmeister , Giovanna Damia , Valerio Fasano , Alessandra Silvani , Clelia Giannini , Daniele Passarella

{"title":"Synthesis of α-fluorocinnamate derivatives as novel cathepsin S inhibitors with in vitro antiproliferative activity against pancreatic cancer cells","authors":"Andrea Citarella , Serena Petrella , Davide Moi , Alessandro Dimasi , Tommaso Braga , Lorenzo Ruberto , Stefano Pieraccini , Maurizio Sironi , Nicola Micale , Tanja Schirmeister , Giovanna Damia , Valerio Fasano , Alessandra Silvani , Clelia Giannini , Daniele Passarella","doi":"10.1016/j.bmc.2024.117987","DOIUrl":"10.1016/j.bmc.2024.117987","url":null,"abstract":"<div><div>Cathepsins, key members of the papain-like family of cysteine proteases, are crucial for proteolysis processes within human cells, including osteolysis, immunomodulation and apoptosis. Recent research has highlighted the significant role of cathepsins, particularly the L, S, K, and B subtypes, in pancreatic cancer. This has driven the development of novel cathepsin inhibitors as potential treatments to inhibit tumor progression, migration and invasion. Targeting cathepsin S (CatS) has shown promise in reducing tumor progression and enhancing the efficacy of chemotherapeutic agents in preclinical models. Building on our previous work where we employed ethyl <em>p</em>-aminocinnamate ester derivatives for covalent inhibition of cysteine proteases, herein we have designed and synthesized three new derivatives basing on an isosteric replacement (H–F) at the level of cinnamate moiety. These derivatives emerged as potent covalent inhibitors of CatS (1.8–2.6 µM) with <strong>2F</strong> showing also weak inhibition activity against CatL (20 %) and CatB (29 %). <em>In vitro</em> assays of <strong>2F</strong> against pancreatic cancer cell lines BXPC3 and CAPAN1 revealed significant antiproliferative activity, with IC<sub>50</sub> = 5.79 µM and 20.75 µM, respectively. These findings underscore the potential of α-fluorocinnamate-based cysteine protease inhibitors as promising candidates for further development in targeting CatS and CatL with the aim to reduce pancreatic cancer cell proliferation.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"115 ","pages":"Article 117987"},"PeriodicalIF":3.3,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142592797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Synthesis and biological evaluation of sugar-modified truncated carbanucleosides as A2A and A3 adenosine receptor ligands to explore conformational effect to the receptors 糖修饰的截短碳核苷作为 A2A 和 A3 腺苷受体配体的合成和生物学评价，以探索对受体的构象效应。

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-11-02 DOI: 10.1016/j.bmc.2024.117986

Minjae Kim , Young Eum Hyun , Seung Yeon Kang , Seung Woo Kim , Jung Hoon Park , Misuk Joung , Lak Shin Jeong

{"title":"Synthesis and biological evaluation of sugar-modified truncated carbanucleosides as A2A and A3 adenosine receptor ligands to explore conformational effect to the receptors","authors":"Minjae Kim , Young Eum Hyun , Seung Yeon Kang , Seung Woo Kim , Jung Hoon Park , Misuk Joung , Lak Shin Jeong","doi":"10.1016/j.bmc.2024.117986","DOIUrl":"10.1016/j.bmc.2024.117986","url":null,"abstract":"<div><div>This study investigated the impact of conformation on the binding affinity of carbanucleosides to A<sub>2A</sub> and A<sub>3</sub> adenosine receptors (ARs). A series of nucleosides, including saturated, unsaturated, North (<em>N</em>)-methano, and South (<em>S</em>)-methanocarbanucleosides was prepared, and their binding affinities to A<sub>2A</sub>AR and A<sub>3</sub>AR were assessed. Biological evaluations revealed that all synthesized (<em>S</em>)-methanocarbanucleosides had negligible binding to both receptors, and most (<em>N</em>)-methanocarbanucleosides exhibited high binding affinities. Molecular docking analysis showed that the (<em>N</em>)-methanocarbanucleoside <strong>6a</strong> exhibited favorable interactions and minimal steric clashes in both A<sub>2A</sub>AR and A<sub>3</sub>AR. Conversely, the (<em>S</em>)-methanocarbanucleoside <strong>7a</strong> appears to encounter significant steric clashes, which impeded its binding to A<sub>2A</sub>AR. Furthermore, when adopting the South conformation <strong>7a</strong> was unable to bind to A<sub>3</sub>AR. Expanding upon the (<em>N</em>)-methanocarba moiety, various C8-aromatic groups were introduced to convert A<sub>2A</sub>AR agonists into antagonists and these modified compounds also exhibited strong binding affinity. These results suggest that the North conformation is favored by both A<sub>2A</sub>AR and A<sub>3</sub>AR, and that (<em>N</em>)-methanocarbanucleosides can serve as versatile structural moieties for dual targeting of A<sub>2A</sub>AR and A<sub>3</sub>AR. These findings offer promising avenues for the development of dual ligands for therapeutic applications in obesity and immunotherapy.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"115 ","pages":"Article 117986"},"PeriodicalIF":3.3,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 therapeutic evaluation of novel antimalarial derivatives based on the clinical antitumor candidate drug Quisinostat 基于临床抗肿瘤候选药物 Quisinostat 的新型抗疟衍生物的设计、合成和治疗评估

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-11-01 DOI: 10.1016/j.bmc.2024.117985

Jiamei Song , Ruoxi Li , Zhenghui Huang , Yunan Qian , Xicheng Wang , Qiqi Shao , Fei Mao , Manjiong Wang , Lubin Jiang , Jian Li , Xiaokang Li

{"title":"Design, synthesis and therapeutic evaluation of novel antimalarial derivatives based on the clinical antitumor candidate drug Quisinostat","authors":"Jiamei Song , Ruoxi Li , Zhenghui Huang , Yunan Qian , Xicheng Wang , Qiqi Shao , Fei Mao , Manjiong Wang , Lubin Jiang , Jian Li , Xiaokang Li","doi":"10.1016/j.bmc.2024.117985","DOIUrl":"10.1016/j.bmc.2024.117985","url":null,"abstract":"<div><div>In previous studies, we identified the clinical antitumor drug candidate Quisinostat is a potent <em>Plasmodium falciparum</em> histone deacetylase (<em>Pf</em>HDAC) inhibitor with significant activity against drug-resistant malaria but with severe toxicity. To delve deeper into its antimalarial potential, herein we designed and synthesized 36 novel analogues of Quisinostat and systematically evaluated their antimalarial activities and cytotoxicity. Among them, compounds <strong>33</strong> and <strong>37</strong> could effectively eliminate both wild-type and multidrug resistant <em>P. falciparum</em> parasites along with significantly attenuated cytotoxicity, and their metabolic properties were also notably improved. Western blot analysis showed that <strong>33</strong> and <strong>37</strong> upregulated <em>Plasmodium</em> histone acetylation, suggesting that they exerted antimalarial effects through inhibition of <em>Pf</em>HDAC like Quisinostat. Furthermore, compounds <strong>33</strong> and <strong>37</strong> also displayed significant antimalarial therapeutic effect and improved animal safety in rodent malaria model. Collectively, <strong>33</strong> and <strong>37</strong> were structurally novel <em>Pf</em>HDAC inhibitors and promising antimalarial lead compounds for the next generation of antimalarial drug research.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"115 ","pages":"Article 117985"},"PeriodicalIF":3.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142592994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Ringing medicinal chemistry: The importance of 3-membered rings in drug discovery 环状药物化学：三元环在药物发现中的重要性。

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-10-31 DOI: 10.1016/j.bmc.2024.117980

Sahani Sandalima Uthumange , Angie Jun Hui Liew , Xavier Wezen Chee , Keng Yoon Yeong

{"title":"Ringing medicinal chemistry: The importance of 3-membered rings in drug discovery","authors":"Sahani Sandalima Uthumange , Angie Jun Hui Liew , Xavier Wezen Chee , Keng Yoon Yeong","doi":"10.1016/j.bmc.2024.117980","DOIUrl":"10.1016/j.bmc.2024.117980","url":null,"abstract":"<div><div>Scaffold-based drug design has become increasingly prominent in the pharmaceutical field due to the systematic and effective approach through which it facilitates the development of novel drugs. The identification of key scaffolds provides medicinal chemists with a fundamental framework for subsequent research. With mounting evidence suggesting that increased aromaticity could impede the chances of developmental success for oral drug candidates, there is an imperative need for a more thorough exploration of alternative ring systems to mitigate attrition risks. The unique characteristics exhibited by three-membered rings have led to their application in medicinal chemistry. This review explores the use of cyclopropane-, aziridine-, thiirane-, and epoxide-containing compounds in drug discovery, focusing on their roles in approved medicines and drug candidates. Specifically, the importance of the three-membered ring systems in rending biological activity for each drug molecule was highlighted. The undeniable therapeutic value and intriguing features presented by these compounds suggest significant pharmacological potential, providing justification for their incorporation into the design of novel drug candidates.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 117980"},"PeriodicalIF":3.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Exploration of novel 20S proteasome activators featuring anthraquinone structures and their application in hypoxic cardiomyocyte protection 探索具有蒽醌结构的新型 20S 蛋白酶体激活剂及其在缺氧性心肌细胞保护中的应用

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-10-31 DOI: 10.1016/j.bmc.2024.117983

Qian Yu , Lixin Gao , Linhao Xu , Yubing Han , Yu Cao , Jianjun Xi , Yigang Zhong , Linjie Li , Liteng Shen , Jinxin Che , Xiaowu Dong , Chong Zhang , Linghui Zeng , Huajian Zhu , Jiaan Shao , Yizhou Xu , Jia Li , Yubo Zhou , Jiankang Zhang

{"title":"Exploration of novel 20S proteasome activators featuring anthraquinone structures and their application in hypoxic cardiomyocyte protection","authors":"Qian Yu , Lixin Gao , Linhao Xu , Yubing Han , Yu Cao , Jianjun Xi , Yigang Zhong , Linjie Li , Liteng Shen , Jinxin Che , Xiaowu Dong , Chong Zhang , Linghui Zeng , Huajian Zhu , Jiaan Shao , Yizhou Xu , Jia Li , Yubo Zhou , Jiankang Zhang","doi":"10.1016/j.bmc.2024.117983","DOIUrl":"10.1016/j.bmc.2024.117983","url":null,"abstract":"<div><div>Under hypoxic conditions, the accumulation of misfolded proteins primarily relies on the autonomous activity of 20S proteasome for degradation. The buildup of toxic proteins in cardiomyocyte contribute to various cardiovascular diseases. Therefore, enhancing the 20S proteasome degradation capacity and restoring protein homeostasis in myocardial cells with small molecule activators represent a promising therapeutic strategy for the treatment of ischemic cardiomyopathy. In this study, the lead compound 8016–8398 was identified through virtual screening, and subsequent structure optimization resulted in a series of highly potent 20S proteasome activators. Intracellular protein degradation assessment revealed that these compounds possessed abilities to alleviate endoplasmic reticulum stress, as demonstrated by the luciferase reporter system. Additionally, selected compound B-03 significantly enhanced the survival rate of hypoxic-damaged cardiomyocytes. Mechanistic investigations verified B-03 rescued hypoxic damaged cardiomyocyte through apoptosis inhibition and proliferation promotion.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"115 ","pages":"Article 117983"},"PeriodicalIF":3.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142578299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 TMPRSS2-PROTACs with florosubstituted 4-guanidino-N-phenylbenzamide derivative ligands 新型 TMPRSS2-PROTAC 与 4-胍基-N-苯基苯甲酰胺衍生物配体的设计、合成和生物学评价。

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-10-31 DOI: 10.1016/j.bmc.2024.117982

Hao Yang , Haoran Xu , Xinxin Lin , Zengxuan Cai , Yong Xia , Yu Wang , Zejie Chen , Koutian Zhang , Yanling Wu , Jianwei Wang , Annoor Awadasseid , Wen Zhang

{"title":"Design, synthesis and biological evaluation of novel TMPRSS2-PROTACs with florosubstituted 4-guanidino-N-phenylbenzamide derivative ligands","authors":"Hao Yang , Haoran Xu , Xinxin Lin , Zengxuan Cai , Yong Xia , Yu Wang , Zejie Chen , Koutian Zhang , Yanling Wu , Jianwei Wang , Annoor Awadasseid , Wen Zhang","doi":"10.1016/j.bmc.2024.117982","DOIUrl":"10.1016/j.bmc.2024.117982","url":null,"abstract":"<div><div>Transmembrane Serine Protease 2 (TMPRSS2) plays a critical role in tumorigenesis and progression, making its degradation a promising therapeutic strategy. In this study, we designed and synthesized TMPRSS2-PROTACs, including <strong>VPOT64</strong> and <strong>VPOT76</strong>, based on camostat. Both compounds exhibited superior inhibitory effects on HT-29 colorectal and Calu-3 lung cancer cells compared to paclitaxel. Notably, <strong>VPOT76</strong> effectively degraded TMPRSS2, significantly inhibiting the proliferation of TMPRSS2-positive HT-29 cells and inducing apoptosis with an IC<sub>50</sub> of 0.39 ± 0.01 μM. Flow cytometry analysis demonstrated that <strong>VPOT76</strong> increased early apoptotic cells in a dose-dependent manner and caused G2 phase arrest at 0.8 μM. Colony formation assays showed that <strong>VPOT76</strong> inhibited HT-29 colony formation, even at low concentrations, further confirming its anti-proliferative effect. Additionally, wound healing assays indicated that <strong>VPOT76</strong> reduced the migration of HT-29 cells after 48 h, suggesting its potential to impair tumor cell invasion and metastasis. These findings highlight the multifaceted anticancer activities of <strong>VPOT76</strong>, including apoptosis induction, cell cycle arrest, colony formation inhibition, and migration suppression. Overall, this study establishes <strong>VPOT76</strong> as a potent TMPRSS2-degrading PROTAC with strong therapeutic potential, laying the groundwork for further development of TMPRSS2-targeting treatments for colorectal and other cancers.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 117982"},"PeriodicalIF":3.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

H2S-releasing oridonin derivatives with improved antitumor activity by inhibiting the PI3K/AKT pathway 通过抑制 PI3K/AKT 通路提高抗肿瘤活性的 H2S 释放型奥利多宁衍生物

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-10-28 DOI: 10.1016/j.bmc.2024.117968

Haonan Li , Qingyinglu Ma , Yufeng Jia , Chao Wang , Jianfei Wu , Siyuan Wang , Huiming Hua , Jincai Lu , Dahong Li

引用次数: 0

Enhancing therapeutic efficacy in homologous recombination-proficient pancreatic cancer via the combination of PARP1-PROTAC and a BRD4 inhibitor 通过联合使用 PARP1-PROTAC 和 BRD4 抑制剂提高同源重组缺陷胰腺癌的疗效。

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-10-26 DOI: 10.1016/j.bmc.2024.117970

Chunlan Pu , Yuanyuan Liu , Suke Lan , Hengrui Fan , Lvye Liu , Jianyu Liu , Yuanbiao Guo

{"title":"Enhancing therapeutic efficacy in homologous recombination-proficient pancreatic cancer via the combination of PARP1-PROTAC and a BRD4 inhibitor","authors":"Chunlan Pu , Yuanyuan Liu , Suke Lan , Hengrui Fan , Lvye Liu , Jianyu Liu , Yuanbiao Guo","doi":"10.1016/j.bmc.2024.117970","DOIUrl":"10.1016/j.bmc.2024.117970","url":null,"abstract":"<div><div>Currently, poly (ADP-ribose) polymerase inhibitors (PARPi) have been approved by U.S. Food and Drug Administration for BRCA-mutated pancreatic cancer therapy. However, limited indications hinder their further application. Repression of bromodomain-containing protein 4 (BRD4) can block the homologous recombination (HR) repair pathway and has the potential to enhance the response to PARPi in HR-proficient pancreatic cancer therapy. In addition, proteolysis targeting chimeras (PROTACs) can hijack E3 ligase within the cell to ubiquitinate degradation-targeted proteins effectively and quickly, thus enhancing the therapeutic effect on tumors. In the present study, the LB23 compound, which induces PARP1 degradation, was employed in combination with the BRD4 inhibitor JQ1, confirming their synergistic effect in HR-proficient pancreatic cancer through various methods. Moreover, compared to the JQ1 and PARPi olaparib combination, PARP1-PROTAC and JQ1 had more notable synergistic effects. Further research into the synergistic mechanism demonstrated that combination therapy enhanced DNA damage and suppressed DNA repair by inducing cell cycle arrest and cell apoptosis. The present study therefore provides the experimental data for this type of combination therapy, which is expected to be an innovative approach for the treatment of HR-proficient pancreatic cancer.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"115 ","pages":"Article 117970"},"PeriodicalIF":3.3,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142542450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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