α-naphthoflavone-derived cytochrome P450 (CYP)1B1 degraders specific for sensitizing CYP1B1-mediated drug resistance to prostate cancer DU145: Structure activity relationship

Chen, Peng; Wang, Shaobing; Cao, Chenyang; Ye, Wenchong; Wang, Meizhu; Zhou, Cui; Chen, Wen-Ming; Zhang, Xu; Zhang, Keyu; Zhou, Wen

doi:10.1016/j.bioorg.2021.105295

Cited by 13 publications

(13 citation statements)

References 31 publications

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“…ssGESA analysis CYP1B1 was associated with melatonergic and immune-related pathways and therapeutic response. Recent studies showed that CYP1B1 was involved in the drug resistance of tumor cells, such as paclitaxel and docetaxel [ 45 , 46 , 47 ]. The clinical trial of CYP1B1-directed vaccination identified that patients with solid and hematologic tumors can benefit from anti-CYP1B1 immunity [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

CYP1B1: A Novel Molecular Biomarker Predicts Molecular Subtype, Tumor Microenvironment, and Immune Response in 33 Cancers

Yuan

Liu

Dai

et al. 2022

Cancers

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Background: Cytochrome P450 Family 1 Subfamily B Member 1 (CYP1B1) is a critical metabolic enzyme of melatonin. Although melatonin has been identified to exhibit tumor suppressing activity, the role and mechanism of the clinical and immunological characteristics of CYP1B1 in cancer remain unclear. Methods: In this study, RNA expression and clinical data were obtained from The Cancer Genome Atlas (TCGA) across 33 solid tumors. The expression, survival, immune subtype, molecular subtype, tumor mutation burden (TMB), microsatellite instability (MSI), biological pathways, and function in vitro and vivo were evaluated. The predictive value of CYP1B1 in immune cohorts was further explored. Results: We found the dysregulated expression of CYP1B1 was associated with the clinical stage and tumor grade. Immunological correlation analysis showed CYP1B1 was positively correlated with the infiltration of lymphocyte, immunomodulator, chemokine, receptor, and cancer-associated fibroblasts (CAFs) in most cancer. Meanwhile, CYP1B1 was involved in immune subtype and molecular subtype, and was connected with TMB, MSI, neoantigen, the activation of multiple melatonergic and immune-related pathways, and therapeutic resistance. Conclusions: Together, this study comprehensively revealed the role and mechanism of CYP1B1 and explored the significant association between CYP1B1 expression and immune activity. These findings provide a promising predictor and molecular target for clinical immune treatment.

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Section: Discussionmentioning

confidence: 99%

CYP1B1: A Novel Molecular Biomarker Predicts Molecular Subtype, Tumor Microenvironment, and Immune Response in 33 Cancers

Yuan

Liu

Dai

et al. 2022

Cancers

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“…The inhibitory effects of the top four compounds on recombinant human CYP1B1 and CYP1A1 enzymes were evaluated using the standard EROD assay, which has been widely used as a method for the assessment of CYP1 inhibitory activity. ,− ANF, a well-known CYP1 inhibitor, was used as a reference drug. The top selected drugs (chlorprothixene, nadifloxacin, glibenclamide, and ticagrelor) were examined at five concentrations as mentioned in the methodology section to investigate their CYP1B1 inhibitory activity.…”

Section: Resultsmentioning

confidence: 99%

Machine Learning Enabled Structure-Based Drug Repurposing Approach to Identify Potential CYP1B1 Inhibitors

et al. 2022

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Drug-metabolizing enzyme (DME)-mediated pharmacokinetic resistance of some clinically approved anticancer agents is one of the main reasons for cancer treatment failure. In particular, some commonly used anticancer medicines, including docetaxel, tamoxifen, imatinib, cisplatin, and paclitaxel, are inactivated by CYP1B1. Currently, no approved drugs are available to treat this CYP1B1-mediated inactivation, making the pharmaceutical industries strive to discover new anticancer agents. Because of the extreme complexity and high risk in drug discovery and development, it is worthwhile to come up with a drug repurposing strategy that may solve the resistance problem of existing chemotherapeutics. Therefore, in the current study, a drug repurposing strategy was implemented to find the possible CYP1B1 inhibitors using machine learning (ML) and structure-based virtual screening (SB-VS) approaches. Initially, three different ML models were developed such as support vector machines (SVMs), random forest (RF), and artificial neural network (ANN); subsequently, the best-selected ML model was employed for virtual screening of the selleckchem database to identify potential CYP1B1 inhibitors. The inhibition potency of the obtained hits was judged by analyzing the crucial active site amino acid interactions against CYP1B1. After a thorough assessment of docking scores, binding affinities, as well as binding modes, four compounds were selected and further subjected to in vitro analysis. From the in vitro analysis, it was observed that chlorprothixene, nadifloxacin, and ticagrelor showed promising inhibitory activity toward CYP1B1 in the IC 50 range of 0.07–3.00 μM. These new chemical scaffolds can be explored as adjuvant therapies to address CYP1B1-mediated drug-resistance problems.

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“…A pressure tube was charged with 2,4-dimethoxythiobenzamide (0.066 g, 0.34 mmol, 1 equiv) and 2-bromo-4-hydroxyacetophenone (0.075 g, 0.34 mmol, 1 equiv), and the general procedure C mentioned above was carried out. Yield: 0.167 g (70% (17). A pressure tube was charged with 16 (0.05 g, 0.16 mmol, 1 equiv) and potassium carbonate (0.033 g, 0.24 mmol, 1.5 equiv), and the solids were dissolved in 5 mL of acetone.…”

Section: 3″55″-tetramethoxy-11′:2′1″-terphenyl (2)mentioning

confidence: 99%

“…In addition, CYP1B1 expression is associated with poor survival in associated cancers. , Thus, highly selective inhibitors for CYP1B1 may serve multiple purposes in treating and preventing drug-resistant cancers. Indeed, inhibition of CYP1B1 in cell culture and murine models demonstrably reverses resistance to chemotherapy. ,− …”

Section: Introductionmentioning

confidence: 99%

Design of Cytochrome P450 1B1 Inhibitors via a Scaffold-Hopping Approach

et al. 2022

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Cytochrome P450 1B1 (CYP1B1) is a potential drug target in cancer research that is overexpressed in several solid tumors but is present only at low levels in healthy tissues. Its expression is associated with resistance to common chemotherapeutics, while inhibitors restore efficacy to these drugs in model systems. The majority of CYP1B1 inhibitors are derived from a limited number of scaffolds, and few have achieved outstanding selectivity against other human CYPs, which could impede clinical development. This study explores a new chemical space for CYP1B1 inhibitors using a scaffold-hopping approach and establishes 2,4-diarylthiazoles as a promising framework for further development. From a small library, compound 15 emerged as the lead, with picomolar CYP1B1 inhibition, and over 19,000-fold selectivity against its relative, CYP1A1. To investigate the activity of 15, molecular dynamics, optical spectroscopy, point mutations, and traditional structure–activity relationships were employed and revealed key interactions important for the development of CYP1B1 inhibitors.

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α-naphthoflavone-derived cytochrome P450 (CYP)1B1 degraders specific for sensitizing CYP1B1-mediated drug resistance to prostate cancer DU145: Structure activity relationship

Cited by 13 publications

References 31 publications

CYP1B1: A Novel Molecular Biomarker Predicts Molecular Subtype, Tumor Microenvironment, and Immune Response in 33 Cancers

CYP1B1: A Novel Molecular Biomarker Predicts Molecular Subtype, Tumor Microenvironment, and Immune Response in 33 Cancers

Machine Learning Enabled Structure-Based Drug Repurposing Approach to Identify Potential CYP1B1 Inhibitors

Design of Cytochrome P450 1B1 Inhibitors via a Scaffold-Hopping Approach

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