BIOORGANIC CHEMISTRY
·
2021
·
IF 5.275
Zhiwen Qi,Guliang Yang,Tao Deng,Jianmin Wang,Hao Zhou,Sergey A. Popov,Elvira E. Shults,Chengzhang Wang
Ursolic acid (UA) is an accessible triterpenoid, widely applied in the design and synthesis of antitumor compounds. However, the mechanism of its anti-tumor effect is still unclear. To verify the molecular mechanism of its biological activity, based on the bifunctional activity of ubiquitination and subsequent proteasomal degradation of the target protein of the proteolysis-targeting chimeras (PROTACs) strategy, here we report the design, synthesis and cellular activity of six UA PROTAC hydrochloride compounds 1A - 1F , in which UA acts as the binding ligand of the PROTAC and is linked to thalidomide (E3 ligand) through a series of synthetic linkers. The results revealed that compound 1B , connected with a POE-3 (3-Polyoxyether) possessed remarkable in vitro antitumor activity (with the IC 50 value of 0.23 ~ 0.39 μM against A549, Huh7, HepG2). WB results demonstrated that the administration of compound 1B induced significant degradation of MDM2 (only 25% to that of SM1), and promoted the expression of P21 and PUMA proteins, and thus inhibited the proliferation (77.67% of 1B vs 60.37% of CON in G1 phase) and promoted the apoptosis (26.74% of 1B vs 3.35% of CON) of A549 cells. This work demonstrated proof of designing the efficient target protein degradation by UA PROTACs with the POE linkers. In addition, we confirmed that UA possess the characteristic of targeted-binding the protein of murine double minute-2 protein (MDM2). This will lay a foundation for the comprehensive utilization of forest natural compound UA.
研究领域:
药理学
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肿瘤学
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化学生物学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
·
2025
·
IF 4.3
Lei Fang,Ruixue Zhu,Meijing Li,Junhui Ma,Sijun Fan,Xuelian He,Zhongrui Yang,Yakai Yan,Xiang Ma,Guangya Xiang
Proteolysis targeting chimeras (PROTACs) technology is a promising strategy for degrading proteins of interest. Traditional PROTACs, however, often face challenges such as poor solubility, low stability, and off-target toxicity. To address these challenges, we integrated nanotechnology to enhance the delivery of target-protein degraders to the tumor sites, thereby improving their properties. Here, we report silica-based nano-PROTACs (SiPROTACs) that feature multiple ligands on the surface to target and degrade the transmembrane protein epidermal growth factor receptor (EGFR). SiPROTACs, with a diameter of approximately 50 nm, can efficiently bind to EGFR, recruit cereblon (CRBN) to induce EGFR ubiquitination, and facilitate their degradation by proteasomes. In HCC-827 and PC-9 cell lines, SiPROTACs initiated EGFR degradation at a notably low concentration of 50 nM, demonstrating greater efficiency compared to traditional PROTACs. In HCC-827 xenograft tumor-bearing mice, SiPROTACs accumulated at tumor site for at least 48 h and exhibited significant anti-tumor effects in vivo without causing noticeable side effects. These findings suggest a novel approach for the application of PROTACs highlighting their therapeutic potential for the treatment of non-small cell lung cancer (NSCLC).
研究领域:
肿瘤学
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药理学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2024
·Vol. 85
·期 5
·e22241
·
IF 3.5
Xiaowen Wang,Linyu Su,Chong Niu,Xiao Li,Ruijie Wang,Bo Li,Sha Liu,Yuwen Xu
The role of KRAS mutation in non-small cell lung cancer (NSCLC) initiation and progression is well-established. However, “undruggable” KRAS protein poses the research of small molecule inhibitors a significant challenge. Addressing this, proteolysis-targeting chimeras (PROTACs) have become a cutting-edge treatment method, emphasizing protein degradation. A modified ethanol injection method was employed in this study to formulate liposomes encapsulating PROTAC drug LC-2 (LC-2 LPs). Precise surface modifications using cell-penetrating peptide R8 yielded R8-LC-2 liposomes (R8-LC-2 LPs). Comprehensive cellular uptake and cytotoxicity studies unveiled that R8-LC-2 LPs depended on concentration and time, showcasing the superior performance of R8-LC-2 LPs compared to normal liposomes. In vivo pharmacokinetic profiles demonstrated the capacity of DSPE-PEG2000 to prolong the circulation time of LC-2, leading to higher plasma concentrations compared to free LC-2. In vivo antitumor efficacy research underscored the remarkable ability of R8-LC-2 LPs to effectively suppress tumor growth. This study contributed to the exploration of enhanced therapeutic strategies for NSCLC, specifically focusing on the development of liposomal PROTACs targeting the “undruggable” KRAS protein. The findings provide valuable insights into the potential of this innovative approach, offering prospects for improved drug delivery and heightened antitumor efficacy.
研究领域:
肿瘤学
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药学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Jianchao Zhang,Xiao Chen,Congli Chen,Fengming Li,Xiaoxiao Song,Chaowei Liu,Kefan Liao,Ming-Yuan Su,Chris Soon Heng Tan,Lijing Fang,Hai Rao
Proteolysis-targeting chimeras (PROTACs) selectively eliminate detrimental proteins by exploiting the ubiquitin-proteasome system (UPS), representing a promising therapeutic strategy against various diseases. Effective adaptations of degradation signal sequences and E3 ligases for PROTACs remain limited. Here, we employed three amino acids─Gly, Pro, and Lys─as the ligand to recruit the corresponding E3 ligases: CRL2ZYG11B/ZER1, GID4, and UBRs, to degrade EML4-ALK and mutant EGFR, two oncogenic drivers in NSCLC. We found that the extent of EML4-ALK and EGFR reduction can be easily fine-tuned by using different degradation signals. These amino acid-based PROTACs, termed AATacs, hindered proliferation and induced cell cycle arrest and apoptosis of NSCLC cells in vitro. Compared to other PROTACs, AATacs are small, interchangeable but with different degradation efficiency. Our study further expands the repertoire of E3 ligases and their ligands for PROTAC application, improving the versatility and utility of targeted protein degradation for therapeutic purposes.
研究领域:
肿瘤学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2024
·
IF 4.5
Kai Wang,Meixu Jiang,Huimin Liu,Chen Meng,Mengyuan Li,Haibin Lu
Reactivating p53 activity to restore its anticancer function is an attractive cancer treatment strategy. In this study, we designed and synthesized a series of novel PROTACs to reactivate p53 via the co-degradation of CK1α and CDK7/9 proteins. Bioactivity studies showed that the selected PROTAC 13i exhibited potency antiproliferative activity in MV4-11 (IC 50 = 0.096 ± 0.012 μM) and MOLM-13 (IC 50 = 0.072 ± 0.014 μM) cells, and induced apoptosis of MV4-11 cells. Western-blot analysis showed that PROTAC 13i triple CK1α and CDK7/9 protein degradation resulted in the significantly increased expression of p53. At the same time, the transcriptional repression due to the degradation significantly reduced downstream gene expression of MYC, MDM2, BCL-2 and MCL-1, and reduced the inflammatory cytokine levels of TNF-α, IL-1β and IL-6 in PMBCs. These results indicate the beneficial impact of simultaneous CK1α and CDK7/9 degradation for acute myeloid leukemia therapy.
研究领域:
肿瘤学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2022
·
IF 16.744
Hao Liu,Chao Chen,Haolin Chen,Luoqi Mo,Zhouyi Guo,Binggang Ye,Zhiming Liu
Proteolytic targeting chimeras (PROTACs) are a strategy for protein degradation through proteasome degradation pathway, which has great potential in nano therapy. However, its degradation efficiency of target protein is low, which could not achieve the expected effect, leading to the failure of this tumor treatment. Herein, Two-dimensional (2D) nanosystems (2D-PROTACs: T-ARV) constructed from tantalum telluride (TaTe 2 ) nanosheets loaded with PROTACs (ARV-825) in order to increase the contact probability between the target protein and E3 ligase and enhance the protein degradation performance. It can realize the efficient degradation of Bromodomain Containing 4 (BRD4) and C-MYC, so as to enhance the photothermal and photodynamic therapy of tumors. Importantly, as a photothermal optical coherence tomography (PT-OCT) contrast agent, T-ARV is able to provide micron-resolution three-dimensional images of tumor tissue, guided multimodal tumor therapy. Therefore, the construction of therapeutic strategies for 2D-PROTACs enables effectively improve the degradation efficiency of protacs to target proteins and enhance the therapeutic effect of nano preparations on tumors.
研究领域:
纳米技术
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癌症治疗
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生物医学工程
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光学成像
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分子生物学
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产品关联
DOI
高影响因子
BIOORGANIC CHEMISTRY
·
2020
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IF 4.831
Zhe Zhou,Jing Long,Yuan Wang,YaYun Li,Xu Zhang,Ling Tang,Qi Chang,Zhuo Chen,GaoYun Hu,Shuo Hu,QianBin Li,Cong Peng,Xiang Chen
CD147 is a transmembrane glycoprotein and a member of immunoglobulin superfamily, is strongly expressed in melanoma cells. CD147 has a pivotal role in tumor development. Therefore, it is a potential drug target for melanoma. In this article, we report the discovery of the first CD147 protein proteolysis targeting chimeras (PROTACs) derived from the natural product pseudolaric acid B (PAB). The representative compound 6a effectively induced degradation of CD147 and inhibited melanoma cells in vitro and in vivo. 6a could be used as the novel type of anticancer agent or as a part of the molecular biology research toolkit used in the gain-of-function study of the dynamic roles of CD147 in cancer networks.
研究领域:
肿瘤学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2019
·
IF 4.833
Yuxuan Dai,Na Yue,Junni Gong,Chunxia Liu,Qifei Li,Jiaqi Zhou,Wenlong Huang,Hai Qian
Proteolysis-targeting chimera (PROTAC) could selectively degrade target protein and may become a promising strategy for treating estrogen receptor α (ERα) positive breast cancers. Here, we designed penetrated peptide-based PROTACs by constructing an N-terminal lactam cyclic to improve proteolytic stability and cell penetration. We used a lactam cyclic peptide as ERα binding ligand , 6-aminocaproic acid as a linker, and a hydroxylated pentapeptide structure for recruiting E3 ligase to obtain heterobifunctional compounds. The resulting optimized compound I-6 selectively recruited ERα to the E3 ligase complex for promoting the degradation of ERα. Compound I-6 possessed strong effect on MCF-7 cell toxicity (IC 50 ∼9.7 μM) and significantly enhanced activities in inducing ERα degradation. Meanwhile, I-6 performed much stronger potency in inhibition of tumors growth than tamoxifen . This work is a successful template to construct PROTACs based on cell-permeable peptides, which could extend the chemical space of PROTACs.
CAS / MDL:
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2026
·
IF 7.3
Junhui Ma,Lei Fang,Yu Wu,Hui Jiao,Guangya Xiang,Xiang Ma
Proteolysis-targeting chimeras (PROTACs) are attractive targeted protein degradation modalities, while their clinical advancement is limited by high molecular weight, suboptimal bioavailability, low cellular permeability, and unsatisfactory in vivo efficacy. Herein, we developed a self-assembled nanoparticle system (PRO NPs) constructed from amphiphilic PROTACs. Owing to their intrinsic amphiphilicity, PRO NPs can spontaneously assemble into stable nanoparticles without external excipients, simplifying fabrication and alleviating carrier-associated toxicity. Compared with the free EGFR-targeting PROTAC, PRO NPs exhibited enhanced aqueous solubility and efficient EGFR degradation in HCC827 cells. In vivo, PRO NPs functionalized with hyaluronic acid (HA) through electrostatic adsorption could actively accumulate at tumor sites via CD44-mediated targeting, exerting potent antitumor efficacy (TGI = 76.8%) with reduced systemic toxicity. Collectively, these findings provide novel insights into nano-PROTAC design and a promising strategy for the development of targeted protein degradation therapies.
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DOI
PubMed
高影响因子
Cell Death & Disease
·
2025
·Vol. 16
·期 1
·1-16
·
IF 9.6
Yang Mengxue,Wang Ting,Shao Jingrong,Ran Xinna,Xiao Rui,Zhao Rui,Wu Chunyan,Ji Ming,Tian Weiping,Sun Huabing,Liu Jiao,Zuo Shengkai
Myocardial infarction (MI) remains one of the leading causes of mortality worldwide, and cardiomyocyte death plays a critical role in cardiac remodeling after MI. Ferroptosis is a recently identified form of iron-dependent programmed cell death that has been shown to be involved in the progression of various cardiovascular diseases, including MI. Bromodomain-containing protein 4 (BRD4) is an epigenetic reader and a key regulator of cell survival. In this study, we screened an epigenetic target library containing 773 small-molecule compounds and found that (+)-JQ-1(hereafter abbreviated as JQ-1), a BRD4-specific inhibitor, markedly attenuated ferroptosis induced by erastin (a ferroptosis inducer) in cardiomyocytes. Both prophylactic and therapeutic JQ-1 administration significantly improved cardiac remodeling and reduced cardiomyocyte ferroptosis in mice with MI. Mechanistically, JQ-1 protected cardiomyocytes from erastin-induced ferroptosis by downregulating the expression of nicotinate phosphoribosyltransferase (NAPRT) and upregulating the expression of nicotinamide phosphoribosyltransferase (NAMPT) and sirtuin1 (SIRT1). Inhibition of NAMPT or SIRT1 abrogated the protection conferred by JQ-1 in erastin-treated H9C2 cardiomyocytes. The combination of proteolysis-targeting chimeras (PROTACs) with JQ-1 (JQ-1-PROTAC) promoted BRD4 protein degradation and rescued erastin-induced ferroptosis in H9C2 cardiomyocytes, and prevented erastin-induced ferroptosis in human cardiomyocytes. Thus, JQ-1 can protect cardiomyocytes from ferroptosis through the NAMPT-SIRT1 pathway, and JQ-1-based therapy may serve as a novel promising strategy to improve cardiac remodeling after MI.
研究领域:
心脏病学
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分子生物学
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药理学
·
细胞死亡
·
表观遗传学
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产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2026
·
IF 11
Xueping Luo,Yixin Liu,Guangmiao Chen,Xinrui Ma,Pingping Xu,Yutong Li,Longyu Zheng,Rongrong Zheng,Youqin Xu,Shiying Li,Linping Zhao
Ferroptosis, a form of regulated cell death that is iron-dependent and driven by the accumulation of lipid peroxides (LPO), has emerged as a promising avenue for enhancing tumor immunogenicity and augmenting immune checkpoint blockade (ICB) efficacy. In this study, we demonstrated that dBET57, a BRD4-targeting PROTAC, potently suppresses the expression of GPX4, the master negative regulator of ferroptosis, thereby triggering ferroptotic cell death, while concurrently downregulating PD-L1 to reverse immune evasion. Based on this, we developed a self-assembled nano-PROTAC platform, termed dBET@TF, designed to amplify ferroptosis and potentiate colorectal cancer immunotherapy. Specifically, dBET@TF was constructed via self-assembly of dBET57, tannic acid, and Fe 3+ , which endowed the formulation with acid-responsive drug release capability and significantly improved its intracellular delivery efficiency. Mechanistically, dBET@TF promoted ferroptosis through iron accumulation and GPX4 depletion, triggering robust immunogenic cell death (ICD). Concurrently, BRD4 degradation mediated by dBET@TF durably suppressed PD-L1 expression, reprogramming the tumor microenvironment to foster enhanced immune activation, characterized by increased infiltration of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). As a result, dBET@TF significantly potentiated the therapeutic response to αPD-1 in both primary tumor and experimental lung metastasis models. Overall, this work establishes a novel PROTAC-based therapeutic strategy that leverages BRD4 degradation to amplify ferroptosis and remodel antitumor immunity, offering a promising approach to potentiate colorectal cancer immunotherapy.
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Xuechun Wang,Jie Yan,Yilei Zhao,Songyan Li,Zilin Ma,Xiuying Duan,Yuelan Wang,Jianwei Jiao,Changping Gu,Guiqiang Zhang
Proteolysis targeting chimera (PROTAC) has recently emerged as a promising strategy to selectively degrade target proteins in the treatment of various diseases. However, it has low bioavailability due to strong hydrophobicity, poor membrane permeability, and nonspecific distribution in vivo, which greatly limits its application. In this study, self-delivery PROTAC nanoparticles (designated as CP NPs) integrating gefitinib-based PROTACs and photosensitizers were developed to efficiently degrade mutated epidermal growth factor receptor (EGFR), a crucial kinase for cell growth and survival, while simultaneously triggering photodynamic therapy and immunotherapy. The prepared NPs enhanced the tumor accumulation of PROTACs, which led to the selective degradation of EGFR mutations and a reduction in programmed cell death protein ligand 1 levels, thereby alleviating tumor immunosuppression and immune tolerance. Moreover, under laser irradiation, the coloaded photosensitizers triggered potent photodynamic therapy effects and induced immunogenic cell death, which worked synergistically with PROTACs toward eliciting a robust antitumor immune response. In a mouse model of lung cancer, primary, distant, and lung metastatic tumors were significantly suppressed. This work highlights the potential of nano-PROTACs for degrading target proteins and facilitating combination photodynamic immunotherapy toward expanding PROTAC applications in cancer therapy.
研究领域:
肿瘤学
·
药理学
·
免疫学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）