Binding patterns and structure–activity relationship of CDK8 inhibitors

Ma, Duo; Chen, Xing; Shen, Xiaobao; Sheng, Liang; Liu, Xin Hua

doi:10.1016/j.bioorg.2020.103624

Cited by 6 publications

(3 citation statements)

References 105 publications

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“…At least one study has shown that loss of CDK8 kinase activity leads to dysregulated NOTCH signaling to promote lymphatic leukemia ( 46 ). It is of importance to note that other studies have investigated the relationship between CDK8 kinase activity and tumorigenesis in a MED12-independent context in a variety of different cancers ( 80 , 81 ). Nonetheless, further studies are required to study the mechanisms behind MED12-mediated loss of CDK8 kinase activity and subsequent tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

The role of mediator subunit 12 in tumorigenesis and cancer therapeutics (Review)

2022

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Mediator complex subunit 12 (MED12) is a subunit of Mediator, a large multi-subunit protein complex that acts an important regulator of transcription. Specifically, MED12 is an integral part of the kinase module of Mediator along with MED13, CyclinC (CycC) and CDK8. Structural studies have indicated that MED12 makes a direct connection to CycC through a specific interface and thereby functions to create a link between MED13 and CycC-CDK8. Disruption of the MED12-CycC interface often leads to dysregulated CDK8 kinase activity, which has important physiological implications. For example, a number of studies have indicated that mutations within MED12 can lead to the formation of benign or malignant tumors, either as a result of MED12-CycC disruption or through distinct independent mechanisms. Furthermore, recent studies have indicated that the N-terminal portion of MED12 forms a direct connection to CDK8. Mutations within MED12 do not appear to disrupt the physical connection to CDK8, but rather abrogate CDK8 kinase activity. Thus, mutations in MED12 can cause disruption of CDK8 kinase activity through two separate mechanisms. The aim of the present review article was to discuss the MED12 mutational landscape in a variety of benign and malignant tumors, as well as the mechanistic basis behind tumorigenesis. Furthermore, the link between MED12 and drug resistance has also been discussed, as well as potential cancer therapeutics related to MED12-altered tumors. Contents 1. Introduction 2. MED12 mutations and tumorigenesis 3. Therapeutics 4. Conclusions

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Section: Discussionmentioning

confidence: 99%

The role of mediator subunit 12 in tumorigenesis and cancer therapeutics (Review)

2022

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“…Indeed, several CDK8/CDK19 inhibitors are in preclinical development, and one-BCD-115-has completed Phase I clinical trials (Trial identifier: NCT03065010), although the results have not yet been posted [198]. Recently, Ma et al reviewed the binding profiles of 24 CDK8 inhibitors and highlighted four methods of identifying new inhibitors, which may be more selective for CDK8 [199].…”

Section: Cdk8 and The Mediator Complexmentioning

confidence: 99%

Unravelling the Role of Kinases That Underpin Androgen Signalling in Prostate Cancer

Miller

Asim

2022

Cells

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The androgen receptor (AR) signalling pathway is the key driver in most prostate cancers (PCa), and is underpinned by several kinases both upstream and downstream of the AR. Many popular therapies for PCa that target the AR directly, however, have been circumvented by AR mutation, such as androgen receptor variants. Some upstream kinases promote AR signalling, including those which phosphorylate the AR and others that are AR-regulated, and androgen regulated kinase that can also form feed-forward activation circuits to promotes AR function. All of these kinases represent potentially druggable targets for PCa. There has generally been a divide in reviews reporting on pathways upstream of the AR and those reporting on AR-regulated genes despite the overlap that constitutes the promotion of AR signalling and PCa progression. In this review, we aim to elucidate which kinases—both upstream and AR-regulated—may be therapeutic targets and require future investigation and ongoing trials in developing kinase inhibitors for PCa.

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“…It can bind with cyclin C (CCNC) to form a CDK8 kinase module, which is a component of the mediator complex to participate in the process of transcription regulation . It has been confirmed that CDK8 is closely related to the occurrence, metastasis, metabolism, and drug resistance of various cancers, so it is considered to be an effective antitumor target. − The research boom for CDK8 inhibitor has lasted long, and CDK8 inhibitors (Figure ) with different structures were developed. However, CDK8 is a basic regulator of a variety of cellular transcription processes, and some researchers have expressed concerns that potent inhibitors targeting CDK8 may bring complex and potential toxic effects when achieving the sustained target inhibition rate required for antitumor activity .…”

Section: Introductionmentioning

confidence: 99%

Discovery and Anti-Inflammatory Activity Evaluation of a Novel CDK8 Inhibitor through Upregulation of IL-10 for the Treatment of Inflammatory Bowel Disease In Vivo

Liu

2022

J. Med. Chem.

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Increasing the anti-inflammatory cytokine interleukin-10 (IL-10) level is a promising strategy to suppress the progression of pathogenic inflammation including inflammatory bowel disease (IBD). Since cyclin-dependent kinase 8 (CDK8) inhibition can upregulate IL-10 abundance in activated myeloid-derived dendritic cells, it is considered to be an effective target for IBD treatment. Here, the complete discovery process of a novel CDK8 inhibitor as an anti-inflammatory agent was described. Starting with wogonin, structure-based optimization and structure−activity relationship (SAR) study were comprehensively carried out, and then lead compound 85 (N-(2-ethylphenyl)-5-(4-(piperazine-1carbonyl)phenyl)nicotinamide) was developed as a potent druglike CDK8 inhibitor upregulating IL-10 both in vivo and in vitro. Also, compound 85 (with CDK8 IC 50 = 56 nM, IL-10 enhancement rate 88%) exhibited effective anti-inflammatory activity in an animal model of IBD. These results confirmed that certain CDK8 inhibitor could be used as an effective anti-IBD drug.

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Binding patterns and structure–activity relationship of CDK8 inhibitors

Cited by 6 publications

References 105 publications

The role of mediator subunit 12 in tumorigenesis and cancer therapeutics (Review)

The role of mediator subunit 12 in tumorigenesis and cancer therapeutics (Review)

Unravelling the Role of Kinases That Underpin Androgen Signalling in Prostate Cancer

Discovery and Anti-Inflammatory Activity Evaluation of a Novel CDK8 Inhibitor through Upregulation of IL-10 for the Treatment of Inflammatory Bowel Disease In Vivo

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