Acta Pharmaceutica Sinica. B最新文献_第9页

AKR1C1 interacts with STAT3 to increase intracellular glutathione and confers resistance to oxaliplatin in colorectal cancer AKR1C1 与 STAT3 相互作用，增加细胞内谷胱甘肽含量，使结肠直肠癌患者对奥沙利铂产生抗药性

IF 14.5 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-09-02 DOI: 10.1016/j.apsb.2024.08.031

Zhiwen Fu, Tingting Wu, Chen Gao, Lulu Wang, Yu Zhang, Chen Shi

{"title":"AKR1C1 interacts with STAT3 to increase intracellular glutathione and confers resistance to oxaliplatin in colorectal cancer","authors":"Zhiwen Fu, Tingting Wu, Chen Gao, Lulu Wang, Yu Zhang, Chen Shi","doi":"10.1016/j.apsb.2024.08.031","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.08.031","url":null,"abstract":"Oxaliplatin (OXA), a platinum-based chemotherapeutic agent, remains a mainstay in first-line treatments for advanced colorectal cancer (CRC). However, the eventual development of OXA resistance represents a significant clinical challenge. In the present study, we demonstrate that the aldo-keto reductase 1C1 (AKR1C1) is overexpressed in CRC cells upon acquisition of OXA resistance, evident in OXA-resistant CRC cell lines. We employed genetic silencing and pharmacological inhibition strategies to establish that suppression of AKR1C1 restores OXA sensitivity. Mechanistically, AKR1C1 interacts with and activates the transcription factor STAT3, which upregulates the glutamate transporter EAAT3, thereby elevating intracellular glutathione levels and conferring OXA resistance. Alantolactone, a potent natural product inhibitor of AKR1C1, effectively reverses this chemoresistance, restricting the growth of OXA-resistant CRC cells both and . Our findings uncover a critical AKR1C1-dependent mechanism behind OXA resistance and propose a promising combinatorial therapeutic strategy to overcome this resistance in CRC.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"26 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263630","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

In situ tumor cell engineering reverses immune escape to enhance immunotherapy effect 原位肿瘤细胞工程逆转免疫逃逸，增强免疫疗法效果

IF 14.5 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-09-02 DOI: 10.1016/j.apsb.2024.08.028

Shujun Liu, Shijun Yuan, Meichen Liu, Jinhu Liu, Shunli Fu, Tong Gao, Shuang Liang, Xinyan Huang, Xinke Zhang, Yongjun Liu, Zipeng Zhang, Na Zhang

{"title":"In situ tumor cell engineering reverses immune escape to enhance immunotherapy effect","authors":"Shujun Liu, Shijun Yuan, Meichen Liu, Jinhu Liu, Shunli Fu, Tong Gao, Shuang Liang, Xinyan Huang, Xinke Zhang, Yongjun Liu, Zipeng Zhang, Na Zhang","doi":"10.1016/j.apsb.2024.08.028","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.08.028","url":null,"abstract":"The underlying cause of low response rates to existing immunotherapies is that tumor cells dominate tumor immune escape through surface antigen deficiency and inducing tumor immunosuppressive microenvironment (TIME). Here, we proposed an tumor cell engineering strategy to disrupt tumor immune escape at the root by restoring tumor cell MHC-I/tumor-specific antigen complex (MHC-I/TSA) expression to promote T-cell recognition and by silencing tumor cell CD55 to increase the ICOSL B-cell proportion and reverse the TIME. A doxorubicin (DOX) and dual-gene plasmid (MAC pDNA, encoding both MHC-I/ASMTNMELM and CD55-shRNA) coloaded drug delivery system (LCPN@ACD) with tumor targeting and charge/size dual–conversion properties was prepared. LCPN@ACD-induced ICD promoted DC maturation and enhanced T-cell activation and infiltration. LCPN@ACD enabled effective expression of MHC-I/TSA on tumor cells, increasing the ability of tumor cell recognition and killing. LCPN@ACD downregulated tumor cell CD55 expression, increased the proportion of ICOSL B cells and CTLs, and reversed the TIME, thus greatly improving the efficacy of PD-1 and CAR-T therapies. The application of this tumor cell engineering strategy eliminated the source of tumor immune escape, providing new ideas for solving the challenges of clinical immunotherapy.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"122 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263631","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

DNMT3A loss drives a HIF-1-dependent synthetic lethality to HDAC6 inhibition in non-small cell lung cancer 在非小细胞肺癌中，DNMT3A 的缺失导致了对 HDAC6 抑制作用的 HIF-1 依赖性合成致死率

IF 14.5 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-09-02 DOI: 10.1016/j.apsb.2024.08.025

Jiayu Zhang, Yingxi Zhao, Ruijuan Liang, Xue Zhou, Zhonghua Wang, Cheng Yang, Lingyue Gao, Yonghao Zheng, Hui Shao, Yang Su, Wei Cui, Lina Jia, Jingyu Yang, Chunfu Wu, Lihui Wang

{"title":"DNMT3A loss drives a HIF-1-dependent synthetic lethality to HDAC6 inhibition in non-small cell lung cancer","authors":"Jiayu Zhang, Yingxi Zhao, Ruijuan Liang, Xue Zhou, Zhonghua Wang, Cheng Yang, Lingyue Gao, Yonghao Zheng, Hui Shao, Yang Su, Wei Cui, Lina Jia, Jingyu Yang, Chunfu Wu, Lihui Wang","doi":"10.1016/j.apsb.2024.08.025","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.08.025","url":null,"abstract":"encodes a DNA methyltransferase involved in development, cell differentiation, and gene transcription, which is mutated and aberrant-expressed in cancers. Here, we revealed that loss of promotes malignant phenotypes in lung cancer. Based on the epigenetic inhibitor library synthetic lethal screening, we found that small-molecule HDAC6 inhibitors selectively killed -defective NSCLC cells. Knockdown of by siRNAs reduced cell growth and induced apoptosis in -defective NSCLC cells. However, sensitive cells became resistant when was rescued. Furthermore, the selectivity to HDAC6 inhibition was recapitulated in mice, where an HDAC6 inhibitor retarded tumor growth established from -defective but not parental NSCLC cells. Mechanistically, loss resulted in the upregulation of through decreasing its promoter CpG methylation and enhancing transcription factor RUNX1 binding. Notably, our results indicated that HIF-1 pathway was activated in -defective cells whereas inactivated by HDAC6 inhibition. Knockout of contributed to the elimination of synthetic lethality between and . Interestingly, HIF-1 pathway inhibitors could mimic the selective efficacy of HDAC6 inhibition in -defective cells. These results demonstrated as an HIF-1-dependent vulnerability of -defective cancers. Together, our findings identify as a potential HIF-1-dependent therapeutic target for the treatment of -defective cancers like NSCLC.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"104 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263632","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

In situ tumor vaccine with optimized nanoadjuvants and lymph node targeting capacity to treat ovarian cancer and metastases 具有优化纳米佐剂和淋巴结靶向能力的原位肿瘤疫苗治疗卵巢癌和转移瘤

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-09-01 DOI: 10.1016/j.apsb.2024.06.003

{"title":"In situ tumor vaccine with optimized nanoadjuvants and lymph node targeting capacity to treat ovarian cancer and metastases","authors":"","doi":"10.1016/j.apsb.2024.06.003","DOIUrl":"10.1016/j.apsb.2024.06.003","url":null,"abstract":"<div><p>Tumor vaccine, a promising modality of tumor immunotherapy, needs to go through the process of tumor antigen generation and loading, antigen drainage to lymph nodes (LNs), antigen internalization by dendritic cells (DCs), DC maturation, and antigen cross-presentation to activate T-cells. However, tumor vaccines are often unable to satisfy all the steps, leading to the limitation of their application and efficacy. Herein, based on a smart nanogel system, an <em>in situ</em> nano-vaccine (CpG@Man-P/Tra/Gel) targeting LNs was constructed to induce potent anti-tumor immune effects and inhibit the recurrence and metastasis of ovarian cancer. The CpG@Man-P/Tra/Gel exhibited MMP-2-sensitive release of trametinib (Tra) and nano-adjuvant CPG@Man-P, which generated abundant <em>in situ</em> depot of whole-cell tumor antigens and formed <em>in situ</em> nano-vaccines with CpG@Man-P. Benefiting from mannose (Man) modification, the nano-vaccines targeted to LNs, promoted the uptake of antigens by DCs, further inducing the maturation of DCs and activation of T cells. Moreover, CpG@Man-P with different particle sizes were prepared and the effective size was selected to evaluate the antitumor effect and immune response <em>in vivo</em>. Notably, combined with PD-1 blocking, the vaccine effectively inhibited primary tumor growth and induced tumor-specific immune response against tumor recurrence and metastasis of ovarian cancer.</p></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 9","pages":"Pages 4102-4117"},"PeriodicalIF":14.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S221138352400234X/pdfft?md5=a0678c7e67c933b10332cc576fc2373e&pid=1-s2.0-S221138352400234X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141413006","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

Recent advances to address challenges in extracellular vesicle-based applications for lung cancer 应对基于细胞外囊泡的肺癌应用挑战的最新进展

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-09-01 DOI: 10.1016/j.apsb.2024.06.010

{"title":"Recent advances to address challenges in extracellular vesicle-based applications for lung cancer","authors":"","doi":"10.1016/j.apsb.2024.06.010","DOIUrl":"10.1016/j.apsb.2024.06.010","url":null,"abstract":"<div><p>Lung cancer, highly prevalent and the leading cause of cancer-related death globally, persists as a significant challenge due to the lack of definitive tumor markers for early diagnosis and personalized therapeutic interventions. Recently, extracellular vesicles (EVs), functioning as natural carriers for intercellular communication, have received increasing attention due to their ability to traverse biological barriers and deliver diverse biological cargoes, including cytosolic proteins, cell surface proteins, microRNA, lncRNA, circRNA, DNA, and lipids. EVs are increasingly recognized as a valuable resource for non-invasive liquid biopsy, as well as drug delivery platforms, and anticancer vaccines for precision medicine in lung cancer. Herein, given the diagnostic and therapeutic potential of tumor-associated EVs for lung cancer, we discuss this topic from a translational standpoint. We delve into the specific roles that EVs play in lung cancer carcinogenesis and offer a particular perspective on how advanced engineering technologies can overcome the current challenges and expedite and/or enhance the translation of EVs from laboratory research to clinical settings.</p></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 9","pages":"Pages 3855-3875"},"PeriodicalIF":14.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211383524002417/pdfft?md5=468026f3f5b8e835e25e1109c77b0c75&pid=1-s2.0-S2211383524002417-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141528649","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

PEGylated bacteria restore intestinal mucosal barrier 聚乙二醇化细菌可恢复肠粘膜屏障

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-09-01 DOI: 10.1016/j.apsb.2024.06.016

引用次数: 0

Glycodiversification of gentamicins through in vivo glycosyltransferase swapping enabled the creation of novel hybrid aminoglycoside antibiotics with potent activity and low ototoxicity 通过体内糖基转移酶交换实现庆大霉素的糖基化，从而创造出具有强效活性和低耳毒性的新型混合氨基糖苷类抗生素

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-09-01 DOI: 10.1016/j.apsb.2024.04.030

{"title":"Glycodiversification of gentamicins through in vivo glycosyltransferase swapping enabled the creation of novel hybrid aminoglycoside antibiotics with potent activity and low ototoxicity","authors":"","doi":"10.1016/j.apsb.2024.04.030","DOIUrl":"10.1016/j.apsb.2024.04.030","url":null,"abstract":"<div><p>Aminoglycosides (AGs) are a class of antibiotics with a broad spectrum of activity. However, their use is limited by safety concerns associated with nephrotoxicity and ototoxicity, as well as drug resistance. To address these issues, semi-synthetic approaches for modifying natural AGs have generated new generations of AGs, however, with limited types of modification due to significant challenges in synthesis. This study explores a novel approach that harness the bacterial biosynthetic machinery of gentamicins and kanamycins to create hybrid AGs. This was achieved by glycodiversification of gentamicins <em>via</em> swapping the glycosyltransferase (GT) in their producer with the GT from kanamycins biosynthetic pathway and resulted in the creation of a series of novel AGs, therefore referred to as genkamicins (GKs). The manipulation of the hybrid biosynthetic pathway enabled the targeted accumulation of different GK species and the isolation and characterization of six GK components. These compounds display retained antimicrobial activity against a panel of World Health Organization (WHO) critical priority pathogens, and GK-C2a, in particular, demonstrates low ototoxicity compared to clinical drugs in zebrafish embryos. This study provides a new strategy for diversifying the structure of AGs and a potential avenue for developing less toxic AG drugs to combat infectious diseases.</p></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 9","pages":"Pages 4149-4163"},"PeriodicalIF":14.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211383524001710/pdfft?md5=61529e2e095077621230da69bf47f420&pid=1-s2.0-S2211383524001710-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140938640","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

Establishing cell suitability for high-level production of licorice triterpenoids in yeast 在酵母中建立高水平甘草三萜类化合物生产的细胞适宜性

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-09-01 DOI: 10.1016/j.apsb.2024.04.032

{"title":"Establishing cell suitability for high-level production of licorice triterpenoids in yeast","authors":"","doi":"10.1016/j.apsb.2024.04.032","DOIUrl":"10.1016/j.apsb.2024.04.032","url":null,"abstract":"<div><p>Yeast has been an indispensable host for synthesizing complex plant-derived natural compounds, yet the yields remained largely constrained. This limitation mainly arises from overlooking the importance of cell and pathway suitability during the optimization of enzymes and pathways. Herein, beyond conventional enzyme engineering, we dissected metabolic suitability with a framework for simultaneously augmenting cofactors and carbon flux to enhance the biosynthesis of heterogenous triterpenoids. We further developed phospholipid microenvironment engineering strategies, dramatically improving yeast's suitability for the high performance of endoplasmic reticulum (ER)-localized, rate-limiting plant P450s. Combining metabolic and microenvironment suitability by manipulating only three genes, <em>NHMGR</em> (NADH-dependent HMG-CoA reductase), <em>SIP4</em> (a DNA-binding transcription factor)and <em>GPP1</em> (Glycerol-1-phosphate phosphohydrolase 1), we enabled the high-level production of 4.92 g/L rare licorice triterpenoids derived from consecutive oxidation of <em>β</em>-amyrin by two P450 enzymes after fermentation optimization. This production holds substantial commercial value, highlighting the critical role of establishing cell suitability in enhancing triterpenoid biosynthesis and offering a versatile framework applicable to various plant natural product biosynthetic pathways.</p></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 9","pages":"Pages 4134-4148"},"PeriodicalIF":14.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211383524001746/pdfft?md5=8e23b04b400ea0396e81f7613810df44&pid=1-s2.0-S2211383524001746-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141058489","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

Identification of novel small-molecule inhibitors of SARS-CoV-2 by chemical genetics 通过化学遗传学鉴定新型 SARS-CoV-2 小分子抑制剂

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-09-01 DOI: 10.1016/j.apsb.2024.05.026

{"title":"Identification of novel small-molecule inhibitors of SARS-CoV-2 by chemical genetics","authors":"","doi":"10.1016/j.apsb.2024.05.026","DOIUrl":"10.1016/j.apsb.2024.05.026","url":null,"abstract":"<div><p>There are only eight approved small molecule antiviral drugs for treating COVID-19. Among them, four are nucleotide analogues (remdesivir, JT001, molnupiravir, and azvudine), while the other four are protease inhibitors (nirmatrelvir, ensitrelvir, leritrelvir, and simnotrelvir-ritonavir). Antiviral resistance, unfavourable drug‒drug interaction, and toxicity have been reported in previous studies. Thus there is a dearth of new treatment options for SARS-CoV-2. In this work, a three-tier cell-based screening was employed to identify novel compounds with anti-SARS-CoV-2 activity. One compound, designated <strong>172</strong>, demonstrated broad-spectrum antiviral activity against multiple human pathogenic coronaviruses and different SARS-CoV-2 variants of concern. Mechanistic studies validated by reverse genetics showed that compound <strong>172</strong> inhibits the 3-chymotrypsin-like protease (3CLpro) by binding to an allosteric site and reduces 3CLpro dimerization. A drug synergistic checkerboard assay demonstrated that compound <strong>172</strong> can achieve drug synergy with nirmatrelvir <em>in vitro</em>. <em>In vivo</em> studies confirmed the antiviral activity of compound <strong>172</strong> in both Golden Syrian Hamsters and K18 humanized ACE2 mice. Overall, this study identified an alternative druggable site on the SARS-CoV-2 3CLpro, proposed a potential combination therapy with nirmatrelvir to reduce the risk of antiviral resistance and shed light on the development of allosteric protease inhibitors for treating a range of coronavirus diseases.</p></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 9","pages":"Pages 4028-4044"},"PeriodicalIF":14.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211383524002193/pdfft?md5=245cd59fcf5f588064c9386d2c790d47&pid=1-s2.0-S2211383524002193-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141528597","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

Molecular glue triggers degradation of PHGDH by enhancing the interaction between DDB1 and PHGDH 分子胶通过增强 DDB1 和 PHGDH 之间的相互作用引发 PHGDH 降解

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2024-09-01 DOI: 10.1016/j.apsb.2024.06.001

{"title":"Molecular glue triggers degradation of PHGDH by enhancing the interaction between DDB1 and PHGDH","authors":"","doi":"10.1016/j.apsb.2024.06.001","DOIUrl":"10.1016/j.apsb.2024.06.001","url":null,"abstract":"<div><p>Cancer stem cells (CSCs) play a pivotal role in tumor initiation, proliferation, metastasis, drug resistance, and recurrence. Consequently, targeting CSCs has emerged as a promising avenue for cancer therapy. Recently, 3-phosphoglycerate dehydrogenase (PHGDH) has been identified as being intricately associated with the regulation of numerous cancer stem cells. Yet, reports detailing the functional regulators of PHGDH that can mitigate the stemness across cancer types are limited. In this study, the novel “molecular glue” LXH-3-71 was identified, and it robustly induced degradation of PHGDH, thereby modulating the stemness of colorectal cancer cells (CRCs) both <em>in vitro</em> and <em>in vivo</em>. Remarkably, LXH-3-71 was observed to form a dynamic chimera, between PHGDH and the DDB1-CRL E3 ligase. These insights not only elucidate the anti-CSCs mechanism of the lead compound but also suggest that degradation of PHGDH may be a more viable therapeutic strategy than the development of PHGDH inhibitors. Additionally, compound LXH-3-71 was leveraged as a novel ligand for the DDB1-CRL E3 ligase, facilitating the development of new PROTAC molecules targeting EGFR and CDK4 degradation.</p></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 9","pages":"Pages 4001-4013"},"PeriodicalIF":14.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211383524002326/pdfft?md5=b3ff21986e576e18d54ba16a83d40e06&pid=1-s2.0-S2211383524002326-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141414127","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