Design, synthesis and evaluation of 6-aryl-indenoisoquinolone derivatives dual targeting ERα and VEGFR-2 as anti-breast cancer agents

Tang, Zhichao; Wu, Cheng-Zhe; Tian-lin, Wang; Lao, Kejing; Wang, Yejun; Liu, Linyi; Muyaba, Moses; Xu, Pei; He, Conghui; Luo, Guoshun; Qian, Zhouyang; Niu, Shaoxiong; Wang, Lijun; Wang, Ying; Xiao, Hong; Qin, You

doi:10.1016/j.ejmech.2016.04.029

Cited by 30 publications

(15 citation statements)

References 34 publications

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“…A mechanistic rationale for its efficacy is not obvious from the known target processes of T (estrogen signaling; Shiau et al, 1998 ) and M (autophagy; Sharma et al, 2012 ). However, the effect of M on estrogen receptor target gene sets ( Figure 3 for MCF7, Figure 3—figure supplement 1B for LNCaP) indicates a moderate anti-estrogen effect, akin to the effect of recently developed novel quinolone derivative estrogen receptor antagonists ( Tang et al, 2016 ; Li et al, 2019b ; Tang et al, 2014 ). This suggests an unexpected overlap in the targets of T and M, even if estrogen receptor represents an ‘off-target’ of M, rather than a primary target, and may contribute in part to the high gene expression correlation we observed.…”

Section: Discussionmentioning

confidence: 97%

“…Finally, we used the Pearson correlation between DEGs in monotherapies to predict synergy of their combination and compared these results to those of DIGRE, the best performing method in the DREAM Challenge 24 akin to the effect of recently developed novel quinolone derivative estrogen receptor antagonists (52)(53)(54). This suggests an unexpected overlap in the targets of T and M, even if estrogen receptor represents an "off-target" of M, rather than a primary target, and may contribute in part to the high gene expression correlation we observed.…”

Section: Predicting Drug Synergy In An Independent Datasetmentioning

confidence: 99%

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The transcriptomic response of cells to a drug combination is more than the sum of the responses to the monotherapies

Diaz

Ahsen

Schaffter

et al. 2020

eLife

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Our ability to discover effective drug combinations is limited, in part by insufficient understanding of how the transcriptional response of two monotherapies results in that of their combination. We analyzed matched time course RNAseq profiling of cells treated with single drugs and their combinations and found that the transcriptional signature of the synergistic combination was unique relative to that of either constituent monotherapy. The sequential activation of transcription factors in time in the gene regulatory network was implicated. The nature of this transcriptional cascade suggests that drug synergy may ensue when the transcriptional responses elicited by two unrelated individual drugs are correlated. We used these results as the basis of a simple prediction algorithm attaining an AUROC of 0.77 in the prediction of synergistic drug combinations in an independent dataset.

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Section: Discussionmentioning

confidence: 97%

Section: Predicting Drug Synergy In An Independent Datasetmentioning

confidence: 99%

The transcriptomic response of cells to a drug combination is more than the sum of the responses to the monotherapies

Diaz

Ahsen

Schaffter

et al. 2020

eLife

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“…Tang et al [31], synthesized and structurally characterized a series of 6-aryl-indeno isoquinolone inhibitors targeting ER α to improve efficacy as compared to tamoxifen. The synthesized derivatives presented good ER α binding affinity and antagonistic activity and also showed excellent anticancer activity against MCF-7 using MTT assay.…”

Section: Introductionmentioning

confidence: 99%

Estrogen alpha receptor antagonists for the treatment of breast cancer: a review

Sharma

Kumar

2018

Chemistry Central Journal

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BackgroundCancer is at present one of the leading causes of death in the world. It accounts for 13% of deaths occurred worldwide and is continuously rising, with an estimated million of deaths up to 2030. Due to poor availability of prevention, diagnosis and treatment of breast cancer, the rate of mortality is at alarming level globally. In women, hormone-dependent estrogen receptor positive (ER+) breast cancer making up approximately 75% of all breast cancers. Hence, it has drawn the extensive attention of researchers towards the development of effective drugs for the treatment of hormone-dependent breast cancer. Estrogen, a female sex hormone has a vital role in the initiation and progression of breast malignancy. Therefore, estrogen receptor is the central target for the treatment of breast cancer.ConclusionIn this review, we have studied various classes of antiestrogens that have been designed and synthesized with selective binding for estrogen alpha receptor (ER). Since estrogen receptor α is mainly responsible for the breast cancer initiation and progression, therefore there is need of promising strategies for the design and synthesis of new therapeutic ligands which selectively bind to estrogen alpha receptor and inhibit estrogen dependent proliferative activity.

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“…However, the effect of M on estrogen receptor target gene sets ( Figure 2F, Figure S4E) indicates a moderate anti-estrogen effect, akin to the effect of recently developed novel quinolone derivative estrogen receptor antagonists (X. Li et al, 2019;Tang et al, 2014Tang et al, , 2016 .…”

Section: Discussionmentioning

confidence: 99%

The transcriptomic response of cells to a drug combination is more than the sum of the responses to the monotherapies

Diaz

Ahsen

Schaffter³

et al. 2019

Preprint

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Our ability to predict the effects of drug combinations is limited, in part by limited understanding of how the transcriptional response of two monotherapies results in that of their combination.We performed the first analysis of matched time course RNAseq profiling of cells treated with both single drugs and their combinations. The transcriptional signature of the synergistic combination we studied had unique gene expression not seen in either constituent monotherapy. This can be explained mechanistically by the sequential activation of transcription factors in time in the gene regulatory network. The nature of this transcriptional cascade suggests that drug synergy may ensue when the transcriptional responses elicited by two unrelated individual drugs are correlated. We used these results as the basis of a simple prediction algorithm attaining an AUROC of 0.84 in the prediction of synergistic drug combinations in an independent dataset.

show abstract

Design, synthesis and evaluation of 6-aryl-indenoisoquinolone derivatives dual targeting ERα and VEGFR-2 as anti-breast cancer agents

Cited by 30 publications

References 34 publications

The transcriptomic response of cells to a drug combination is more than the sum of the responses to the monotherapies

The transcriptomic response of cells to a drug combination is more than the sum of the responses to the monotherapies

Estrogen alpha receptor antagonists for the treatment of breast cancer: a review

The transcriptomic response of cells to a drug combination is more than the sum of the responses to the monotherapies

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