Design and synthesis of α-naphthoflavone chimera derivatives able to eliminate cytochrome P450 (CYP)1B1-mediated drug resistance via targeted CYP1B1 degradation

Zhou, Li; Chen, Wen-Ming; Cao, Chenyang; Shi, Yantao; Ye, Wenchong; Hu, Jiliang; Wang, Lingli; Zhou, Wen

doi:10.1016/j.ejmech.2019.112028

Cited by 36 publications

(15 citation statements)

References 30 publications

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“…This reaction has been used to expedite PROTAC synthesis in a highly convergent manner by using an alkyne moiety conjugated to one ligand and an azide conjugated to the other. This approach has proven valuable for optimising diverse libraries of PROTACs with variation in linker length, composition, site of conjugation, or conjugation vector [ 49 , 85 , 86 ]. Wurz et al [ 87 ], probed the effects of linker length and ligase ligand on a series of BRD4 targeting PROTACs ( Figure 11 ).…”

Section: Current Elements Of Protac Linker Designmentioning

confidence: 99%

Current strategies for the design of PROTAC linkers: a critical review

Troup

Fallan

Baud

2020

Exploration of Targeted Anti-Tumor Therapy

218

182

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PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules consisting of two ligands; an “anchor” to bind to an E3 ubiquitin ligase and a “warhead” to bind to a protein of interest, connected by a chemical linker. Targeted protein degradation by PROTACs has emerged as a new modality for the knock down of a range of proteins, with the first agents now reaching clinical evaluation. It has become increasingly clear that the length and composition of the linker play critical roles on the physicochemical properties and bioactivity of PROTACs. While linker design has historically received limited attention, the PROTAC field is evolving rapidly and currently undergoing an important shift from synthetically tractable alkyl and polyethylene glycol to more sophisticated functional linkers. This promises to unlock a wealth of novel PROTAC agents with enhanced bioactivity for therapeutic intervention. Here, the authors provide a timely overview of the diverse linker classes in the published literature, along with their underlying design principles and overall influence on the properties and bioactivity of the associated PROTACs. Finally, the authors provide a critical analysis of current strategies for PROTAC assembly. The authors highlight important limitations associated with the traditional “trial and error” approach around linker design and selection, and suggest potential future avenues to further inform rational linker design and accelerate the identification of optimised PROTACs. In particular, the authors believe that advances in computational and structural methods will play an essential role to gain a better understanding of the structure and dynamics of PROTAC ternary complexes, and will be essential to address the current gaps in knowledge associated with PROTAC design.

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Section: Current Elements Of Protac Linker Designmentioning

confidence: 99%

Current strategies for the design of PROTAC linkers: a critical review

Troup

Fallan

Baud

2020

Exploration of Targeted Anti-Tumor Therapy

218

182

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“…We were particularly interested in CYP1B1 due to the high fold change (log 2 FC = 4.45) and peak enrichment (fold enrich-ment=5.08). The expression of CYP1B1 was significantly higher in tumor tissues than in normal tissues, such as breast, ovarian and prostate tumors [15][16][17], and CYP1B1 functions as an oncogene that promotes tumor progression in multiple tumors [18,19]. Moreover, there were reports indicating that CYP1B1 could promote cell proliferation and metastasis by activating Wnt/ β-catenin pathway [9,10].…”

Section: Znf276 Directly Binds To the Promoter Of Cyp1b1 And Activate...mentioning

confidence: 99%

ZNF276 promotes the malignant phenotype of breast carcinoma by activating the CYP1B1-mediated Wnt/β-catenin pathway

Lei

Zhang

et al. 2022

Cell Death Dis

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Zinc finger proteins (ZNFs) have been demonstrated to participate extensively in breast cancer progression by functioning as transcription factors, but there are still a variety of ZNFs whose biological mechanisms remain unknown. Here, we show that zinc finger protein 276 (ZNF276) is highly expressed in breast cancer tissues and cell lines. Higher level of ZNF276 correlated with poor prognosis. Gain-of and loss-of function suggested that ZNF276 is essential for the proliferation, migration and invasion of breast cancer cells in vitro and metastasis in vivo. RNA-sequencing and CUT&Tag assay revealed that ZNF276 controlled a variety of growth and metastasis-related genes expression. ZNF276 transcriptionally promoted the expression of CYP1B1 by directly binds to the promoter region of the CYP1B1 through its C2H2 domain. ZNF276 facilitated the translocation of β-catenin from cytoplasm to nucleus through CYP1B1, leading to the upregulation of cyclin D1 and c-Myc, and the activation of the Wnt/β-catenin pathway. Knockdown of CYP1B1 significantly blocked the ZNF276-mediated effects on cell proliferation, migration and invasion. Lastly, ZNF276 interacted with MAGEB2 which enhanced the binding of ZNF276 at the CYP1B1 promoter, promoted CYP1B1 expression and Wnt signaling activation. Collectively, these findings highlight the oncogenic role of ZNF276 on breast cancer cell proliferation and metastasis. Targeting ZNF276/MAGEB2 axis may serve as a potential therapeutic strategy for breast cancer patients.

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“…For example, in gastric cancer, overexpression of CYP1B1 can increase its resistance to cisplatin [ 29 ]. Meanwhile, elevated CYP1B1 levels enhance the resistance of ovarian and prostate cancer cells to paclitaxel [ 30 , 31 ]. In particular, the role and mechanism of CYP1B1 in the treatment failure of bicalutamide and in the progression of CRPC have not been reported.…”

Section: Introductionmentioning

confidence: 99%

CYP1B1-catalyzed 4-OHE2 promotes the castration resistance of prostate cancer stem cells by estrogen receptor α-mediated IL6 activation

Lin

Cao

et al. 2022

Cell Commun Signal

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Background Resistance to androgen deprivation therapy remains a major challenge for the clinical treatment of patients with castration-resistant prostate cancer (CRPC). CYP1B1, a critical enzyme that catalyzes the conversion of estradiol to 4-Hydroxy-17β-estradiol (4-OHE2), has been reported to promote the development and progression of hormone-related cancer, but its role in CRPC is unclear. Methods To explore the underlying mechanism which CYP1B1 promotes the prostate cancer stem cells (PCSCs) characteristics, bioinformatics analyses of human clinical prostate cancer (PCa) datasets were performed. CYP1B1, IL6, and estrogen receptor-α (ERα) expression levels were evaluated in PCa and CRPC tissues via immunohistochemistry. The high-performance liquid chromatography-mass spectrometry assay was carried out to examine intracellular 4-OHE2 levels. Serum-free suspension culture and flow cytometry assays were performed to evaluate PCSCs. Chromatin immunoprecipitation was used to validate that 4-OHE2 recruited ERα to the IL6 promoter. Results CYP1B1 expression was significantly increased in CRPC tissues and androgen-independent PCa cell lines. CYP1B1+ PCa cells were significantly enriched in bicalutamide-treated LNCaP cells, and CYP1B1 knockdown reduced the cell viability under bicalutamide treatment. In addition, CYP1B1 knockdown decreased the intracellular 4-OHE2 concentration, accompanied by reduced PCSC characteristics. In PCa cells, 4-OHE2 stimulated ERα transcriptional activity and upregulated the expression of IL6 and downstream genes of the IL6-STAT3 signaling. 4-OHE2 increased cell viability under bicalutamide treatment and promoted PCSC characteristics, while IL6 neutralizing antibody reversed these effects. Mechanistically, siERα and the ER antagonist ICI182780 significantly attenuated 4-OHE2-induced IL6 expression, and 4-OHE2 promoted the binding of ERα to the estrogen response element of the IL6 promoter. Conclusions Our findings indicate that CYP1B1-catalyzed 4-OHE2 enhanced PCSC characteristics and attenuated bicalutamide sensitivity by ERα-mediated the IL6-STAT3 pathway activation. Our study further emphasizes the role of CYP1B1 in castration resistance and illustrates a novel mechanism of CRPC development. Graphical Abstract

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Design and synthesis of α-naphthoflavone chimera derivatives able to eliminate cytochrome P450 (CYP)1B1-mediated drug resistance via targeted CYP1B1 degradation

Cited by 36 publications

References 30 publications

Current strategies for the design of PROTAC linkers: a critical review

Current strategies for the design of PROTAC linkers: a critical review

ZNF276 promotes the malignant phenotype of breast carcinoma by activating the CYP1B1-mediated Wnt/β-catenin pathway

CYP1B1-catalyzed 4-OHE2 promotes the castration resistance of prostate cancer stem cells by estrogen receptor α-mediated IL6 activation

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