ACS Chemical Biology最新文献_第7页

Toyaburgine, a Synthetic N-Biphenyl-Dihydroisoquinoline Inspired by Related N,C-Coupled Naphthylisoquinoline Alkaloids, with High In Vivo Efficacy in Preclinical Pancreatic Cancer Models. Toyaburgine，一种基于N， c偶联萘异喹啉生物碱的合成N-联苯-二氢异喹啉，在临床前胰腺癌模型中具有很高的体内疗效。

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-04-18 Epub Date: 2025-03-06 DOI: 10.1021/acschembio.4c00870

Suresh Awale, Juthamart Maneenet, Nguyen Duy Phan, Hung Hong Nguyen, Tsutomu Fujii, Heiko Ihmels, Denisa Soost, Nasir Tajuddeen, Doris Feineis, Gerhard Bringmann

{"title":"Toyaburgine, a Synthetic N-Biphenyl-Dihydroisoquinoline Inspired by Related N,C-Coupled Naphthylisoquinoline Alkaloids, with High In Vivo Efficacy in Preclinical Pancreatic Cancer Models.","authors":"Suresh Awale, Juthamart Maneenet, Nguyen Duy Phan, Hung Hong Nguyen, Tsutomu Fujii, Heiko Ihmels, Denisa Soost, Nasir Tajuddeen, Doris Feineis, Gerhard Bringmann","doi":"10.1021/acschembio.4c00870","DOIUrl":"10.1021/acschembio.4c00870","url":null,"abstract":"Pancreatic cancer is a highly aggressive and lethal malignancy, with a 5-year survival rate below 10%. Traditional chemotherapy, including gemcitabine, has limited efficacy due to chemoresistance and a unique tumor microenvironment characterized by hypovascularity and nutrient deprivation. This study reports on the discovery of a new N-biphenyl-dihydroisoquinoline, named toyaburgine (4), inspired by naturally occurring N,C-coupled naphthylisoquinoline alkaloids. Developed through systematic structural optimization, toyaburgine is a potent anticancer agent, showing promise for pancreatic cancer treatment. It exhibits strong antiausterity activity with low nanomolar PC50 values, effectively inhibiting pancreatic cancer cell viability under nutrient-deprived conditions. In vitro, 4 causes significant morphological changes and cancer cell death in MIA PaCa-2 cells while also inhibiting cell migration and colony formation, which indicates its antimetastatic potential. Mechanistically, toyaburgine disrupts the PI3K/Akt/mTOR pathway, essential for pancreatic cancer cell survival in a stressful microenvironment, and inhibits MIA PaCa-2 spheroid formation. In vivo, toyaburgine, alone or combined with gemcitabine, shows effective tumor suppression in subcutaneous xenograft and clinically relevant orthotopic models, where it also reduces cachexia. These results highlight the potential of toyaburgine as a new therapeutic drug for pancreatic cancer. Its combination with gemcitabine presents a promising treatment approach by targeting both proliferating and gemcitabine-resistant cancer cells.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"917-929"},"PeriodicalIF":3.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Augmented Acyl-CoA Biosynthesis Promotes Resistance to TEAD Palmitoylation Site Inhibition. 增强酰基辅酶a生物合成促进对TEAD棕榈酰化位点抑制的抗性。

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-04-18 Epub Date: 2025-04-03 DOI: 10.1021/acschembio.5c00162

Kayla Nutsch, Marissa N Trujillo, Lirui Song, Michael A Erb, Jian Jeffery Chen, James J Galligan, Michael J Bollong

引用次数: 0

Optimizing Peptide-Conjugated Lipid Nanoparticles for Efficient siRNA Delivery across the Blood-Brain Barrier and Treatment of Glioblastoma Multiforme. 多形性胶质母细胞瘤的多形性优化肽偶联脂质纳米颗粒的高效siRNA传递通过血脑屏障和治疗。

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-04-18 Epub Date: 2025-03-13 DOI: 10.1021/acschembio.5c00039

Haiyang Tong, Zesen Ma, Jin Yu, Dongsheng Li, Qingjun Zhu, Huajian Shi, Yun Wu, Hongyi Yang, Yanmin Zheng, Demeng Sun, Pan Shi, Jiaru Chu, Pei Lv, Baoqing Li, Changlin Tian

{"title":"Optimizing Peptide-Conjugated Lipid Nanoparticles for Efficient siRNA Delivery across the Blood-Brain Barrier and Treatment of Glioblastoma Multiforme.","authors":"Haiyang Tong, Zesen Ma, Jin Yu, Dongsheng Li, Qingjun Zhu, Huajian Shi, Yun Wu, Hongyi Yang, Yanmin Zheng, Demeng Sun, Pan Shi, Jiaru Chu, Pei Lv, Baoqing Li, Changlin Tian","doi":"10.1021/acschembio.5c00039","DOIUrl":"10.1021/acschembio.5c00039","url":null,"abstract":"Glioblastoma multiforme (GBM) is a WHO grade 4 glioma and the most common malignant primary brain tumor. Addressing the clinical management of GBM presents an exceptionally daunting and intricate challenge, particularly in overcoming the blood-brain barrier (BBB) to deliver effective therapies to the brain. Nanotechnology-based drug delivery systems have exhibited considerable promise in tackling this aggressive brain cancer. However, the BBB remains a key challenge in achieving effective brain delivery of nanocarriers. Here, we have optimized a lipid nanoparticle (LNP) formulation (C2) and modified the LNP with Angiopep-2 peptide, which exhibits the most significant improvements in blood-brain barrier penetration and brain accumulation (about 2.23% injection dose). Using the Ang-2-coupled C2 LNP formulation, we researched the therapeutic effect of Polo-like Kinase 1(PLK1)-targeted siRNA delivery to treat a mouse model of GBM. The optimized LNP formulation was demonstrated to significantly inhibit mouse GBM growth and extend the median survival of mice (2.18-fold). This work demonstrates the efficacy of a brain-targeted siRNA delivery system in GBM treatment. As the understanding of the role of RNAs in GBM deepens and innovative delivery methods are continually developed and refined, RNA-based therapies could emerge as a crucial breakthrough in the advancement of brain tumor treatment.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"942-952"},"PeriodicalIF":3.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dynamic Regulation of 5-Formylcytidine on tRNA. 5-甲酰基胞苷对tRNA的动态调控。

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-04-18 Epub Date: 2025-03-13 DOI: 10.1021/acschembio.4c00866

Xuemeng Sun, Ralph E Kleiner

引用次数: 0

Discovery of Chemical Tools for Polysorbate-Degradative Enzyme Control in the Biopharmaceutical Upstream Process via Multi-Omic Profiling of Host Cell Clones. 通过宿主细胞克隆的多组学分析发现生物制药上游过程中聚山梨酸-降解酶控制的化学工具。

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-04-18 DOI: 10.1021/acschembio.5c00081

Taku Tsukidate, Ansuman Sahoo, Geetanjali Pendyala, Rong-Sheng Yang, Jonathan Welch, Sri Madabhushi, Xuanwen Li

{"title":"Discovery of Chemical Tools for Polysorbate-Degradative Enzyme Control in the Biopharmaceutical Upstream Process via Multi-Omic Profiling of Host Cell Clones.","authors":"Taku Tsukidate, Ansuman Sahoo, Geetanjali Pendyala, Rong-Sheng Yang, Jonathan Welch, Sri Madabhushi, Xuanwen Li","doi":"10.1021/acschembio.5c00081","DOIUrl":"https://doi.org/10.1021/acschembio.5c00081","url":null,"abstract":"Host cell proteins are process-related impurities in biotherapeutics and can potentially pose risks to patient safety and product quality. Specifically, certain host cell-derived enzymes, including lipases, can degrade the formulation excipient polysorbate (PS) in biopharmaceutical formulations, affecting drug product stability in liquid formulations. We leveraged multiomics approaches, including transcriptomics, proteomics, and activity-based protein profiling (ABPP), to identify mechanisms that regulate PS-degradative enzyme (PSDE) abundance and to develop strategies for their control. Comparative multiomics analysis of two monoclonal antibody (mAb)-producing host cell clones revealed differential lipase profiles at the mRNA, protein, and enzyme activity levels and associated increased lipase activity with upregulated lipid catabolic pathways such as the fatty acid beta oxidation pathway. Further, for the first time in the literature, we identified peroxisome proliferator-activated receptor γ (PPARγ) as a key regulator of PSDEs in manufacturing Chinese Hamster Ovary (CHO) cells. Downregulation of the PPARγ pathway with its antagonists resulted in a selective reduction of PSDE levels and improved PS stability without compromising mAb productivity or quality. This study highlights the potential of PPARγ modulators as chemical tools for PSDE control at the gene regulation level, offering significant implications for biopharmaceutical process development and control.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Reengineering of Circularly Permuted Caspase-2 to Enhance Enzyme Stability and Enable Crystallographic Studies. 循环排列Caspase-2的重组以提高酶的稳定性和晶体学研究。

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-04-18 Epub Date: 2025-03-21 DOI: 10.1021/acschembio.4c00795

Jessica L Fuller, Ke Shi, Steffen Pockes, Barry C Finzel, Karen H Ashe, Michael A Walters

{"title":"Reengineering of Circularly Permuted Caspase-2 to Enhance Enzyme Stability and Enable Crystallographic Studies.","authors":"Jessica L Fuller, Ke Shi, Steffen Pockes, Barry C Finzel, Karen H Ashe, Michael A Walters","doi":"10.1021/acschembio.4c00795","DOIUrl":"10.1021/acschembio.4c00795","url":null,"abstract":"Caspase activation has been linked to several diseases, including cancer, neurodegeneration, and inflammatory conditions, generating interest in targeting this family of proteases for drug development. Caspase-2 (Casp2) in particular has been implicated in Alzheimer's Disease (AD) by cleaving tau protein into fragment Δtau314, which reversibly impairs cognitive and synaptic function. Thus, Casp2 inhibition could be a useful strategy for therapeutic treatment of AD. To that end, we have previously synthesized and characterized various series of peptide and peptidomimetic inhibitors that demonstrate potency and selectivity for Casp2 over caspase-3 (Casp3). Despite promising developments in the design of selective Casp2 inhibitors, low expression yields of Casp2 hinder crystallographic experiments and make structure-based design challenging. The design of circularly permuted (cp) Casp2 increased protein yields considerably; however, this protein could not be crystallized. This article describes the characterization of ten novel cpCasp2 mutants, designed with the goal of increasing stability and facilitating crystallization. Gratifyingly, engineered mutant JF1cpCasp2 displayed high relative stability and was readily crystallizable with the canonical Casp2 inhibitor AcVDVAD-CHO, leading to what we believe to be the first crystal structures of any reverse caspase in the PDB. Moreover, we have reported the structure of JF1cpCasp2 with our recently described Casp2-selective inhibitor MUR-65, which revealed a unique interaction with Arg417 in the binding pocket. Overall, JF1cpCasp2 has proven valuable for structure-based design and expanding understanding of Casp2 inhibition, with potential implications for drug discovery and the development of more selective compounds.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"845-857"},"PeriodicalIF":3.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Engineering the Specificity of Acetyl-CoA Synthetase for Diverse Acyl-CoA Thioester Generation. 乙酰辅酶a合成酶对不同乙酰辅酶a硫酯生成的特异性工程研究。

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-04-18 Epub Date: 2025-04-02 DOI: 10.1021/acschembio.5c00014

Jared R Cossin, Thaddeus Q Paulsel, Kim Castelli, Breck Wcisel, Alexandra A Malico, Gavin J Williams

引用次数: 0

Chitinivorax: The New Kid on the Block of Bacterial 2-Alkyl-4(1H)-quinolone Producers. Chitinivorax：细菌2-烷基-4(1H)-喹诺酮类化合物的新产物。

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-04-18 Epub Date: 2025-03-27 DOI: 10.1021/acschembio.5c00046

Viktoriia Savchenko, Xiaoqian Annie Yu, Martin F Polz, Thomas Böttcher

引用次数: 0

Formation of the i-motif Structures by Human Telomeric c-Rich Sequences d(CCCTAA)n and Its Recognition by Bisbenzylisoquinoline Alkaloids. 人类富c端粒序列d(CCCTAA)n i基序结构的形成及其对双苄基异喹啉生物碱的识别。

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-04-18 Epub Date: 2025-03-27 DOI: 10.1021/acschembio.4c00844

Junliu Huang, Zexuan Lin, Jishun Yang, Huining Tang, Yang Yang, Yi Tang, Feixian Luo, Wenshu Wang, Xiaojie Cui

{"title":"Formation of the i-motif Structures by Human Telomeric c-Rich Sequences d(CCCTAA)n and Its Recognition by Bisbenzylisoquinoline Alkaloids.","authors":"Junliu Huang, Zexuan Lin, Jishun Yang, Huining Tang, Yang Yang, Yi Tang, Feixian Luo, Wenshu Wang, Xiaojie Cui","doi":"10.1021/acschembio.4c00844","DOIUrl":"10.1021/acschembio.4c00844","url":null,"abstract":"The human telomeric repeat CCCTAA has been reported to form a higher-order structure called an intercalated motif (i-motif) that plays important roles in telomere function and telomerase activity regulation, and small molecule ligands targeting human telomeric i-motif (hTelo-iM) is a promising therapeutic strategy for cancer treatment, yet the i-motif folding pattern of long CCCTAA repeats and the hTelo-iM ligand screening have not been studied extensively. In this study, we systematically investigated the i-motif structures formed by four and eight telomeric C-rich repeats d(CCCTAA)4 (hTeloC-24mer) and d(CCCTAA)8 (hTeloC-48mer) under varied conditions and found that the long hTeloC-48mer probably forms unstacked tandem i-motif consisting of two hTeloC-24mer i-motif monomers under near physiological conditions. Moreover, natural bisbenzylisoquinoline (BBI) alkaloids, isofangchinoline, fangchinoline, cepharanthine, and tetrandrine, were screened from 33 natural small molecules to effectively disrupt and destabilize the hTelo-iM structures mainly through major groove hydrogen bonding and van der Waals interactions. Further, telomerase repeated amplification protocol (TRAP) assay suggested that the selected BBI alkaloids can inhibit the telomere extension by telomerase. These findings provide a theoretical basis for further telomere structure research as well as a novel class of natural small molecule compounds regulating the hTelo-iM structure and telomerase activity, which may contribute to the anticancer drug design and strategy development taking the hTelo-iM as a target.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"870-879"},"PeriodicalIF":3.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MYC-Targeting PROTACs Lead to Bimodal Degradation and N-Terminal Truncation. 靶向myc的PROTACs导致双峰降解和n端截断。

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-04-18 Epub Date: 2025-03-27 DOI: 10.1021/acschembio.4c00864

Shelton R Boyd, Srinivas Chamakuri, Alexander J Trostle, Hu Chen, Zhandong Liu, Antrix Jian, Jian Wang, Anna Malovannaya, Damian W Young

{"title":"MYC-Targeting PROTACs Lead to Bimodal Degradation and N-Terminal Truncation.","authors":"Shelton R Boyd, Srinivas Chamakuri, Alexander J Trostle, Hu Chen, Zhandong Liu, Antrix Jian, Jian Wang, Anna Malovannaya, Damian W Young","doi":"10.1021/acschembio.4c00864","DOIUrl":"10.1021/acschembio.4c00864","url":null,"abstract":"MYC is a master regulatory transcription factor whose sustained dysregulation promotes the initiation and maintenance of numerous cancers. While MYC is a regarded as a potenial therapeutic target in cancer, its intrinsically disordered structure has proven to be a formidable barrier toward the development of highly effective small molecule inhibitors. We rationalized that proteolysis targeting chimeras (PROTACs), which might accomplish the targeted degradation of MYC, would achieve more potent cell killing in MYC-driven cancer cells than reversible inhibitors. PROTACs are bifunctional small molecules designed to produce a ternary complex between a target protein and an E3 ligase leading the target's ubiquitination and degradation by the 26S proteasome. We generated PROTAC MTP3 based on modifications of the previously reported MYC-targeting compound KJ-Pyr-9. We found that MTP3 depletes endogenous full-length MYC proteins and uniquely induces increasing levels of a functional, N-terminally truncated MYC species, tMYC. Furthermore, MTP3 perturbs cellular MYC levels in favor of a tMYC-dominated state whose gene regulatory landscape is not significantly altered compared to that of wild type MYC. Moreover, although it lacks ∼10 kDa of MYC's N-terminal transactivation domain, tMYC is sufficient to maintain an oncogenic proliferative state. Our results highlight the complexities of proximity-inducing compounds against highly regulated and conformationally dynamic protein targets such as MYC and indicate that PROTACs can induce alternative outcomes beyond target protein degradation.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"896-906"},"PeriodicalIF":3.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143726998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0