Elsevier

Bioorganic Chemistry

Volume 96, March 2020, 103624
Bioorganic Chemistry

Binding patterns and structure–activity relationship of CDK8 inhibitors

https://doi.org/10.1016/j.bioorg.2020.103624Get rights and content

Highlights

  • •

    CDK8 inhibitors were reviewed.

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    Binding information of typical CDK8 inhibitors were discovered.

  • •

    Effective binding regions were discovered.

Abstract

A major goal of medicinal chemists is to identify and validate novel and effective kinase targets for treatment of cancer. Recent studies have shown that cyclin-dependent kinase 8 (CDK8) is a target for treatment of colorectal, breast, melanoma, and prostate cancers. The crystal structure of CDK8 has been reported, and eutectic interactions have been identified for 24 compounds that target CDK8. To more effectively develop CDK8 inhibitors, particularly those with improved selectivity, we summarized the structure, structure–activity relationships, and binding information of typical CDK8 inhibitors, which may serve as a reference for development of novel CDK8 inhibitors.

Graphical abstract

In this review, we have summarized the biological functions of CDK8 and assessed the research results of the past 20 years, regarding the development the structure, structure–activity relationships, and binding informations of typical CDK8 inhibitors.

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Introduction

Currently, protein kinases are the key drug targets under investigation in the field of medicinal chemistry and the development of protein kinase inhibitors is of particular interest for cancer drug discovery. Protein kinases are involved in almost every aspect of cell biology. Numerous human diseases, and particularly diseases that cause tumor development, are caused by mutations in protein kinases [1], [2]. Since the approval of the BCR-ABL inhibitor Gleevec for the treatment of CML by the FDA in 2001, close to 30 small-molecule kinase inhibitors have been approved for cancer treatment [3], [4].

The CDK family of serine/threonine kinases plays an integral role in the process of cell cycle regulation. It also has pivotal functions in transcription, apoptosis, differentiation, and neuronal development [5], [6]. Most CDKs have no independent functions and are only effective when they bind to a specific cyclin. The expression level of CDK fluctuates throughout the cell cycle to both ensure an equilibrium between protein synthesis and degradation and allow activation of CDKs. Therefore, CDKs are promising targets for the inhibition of cancer cell functions. Based on this knowledge, a wide range of small-molecule CDK inhibitors have been synthesized and studied.

Cyclin-dependent kinase 8 (CDK8) is a special subtype of the CDK family [7]. In the nucleus, CDK8 is assembled with MED 12, MED 13, and Cyc C into a large protein complex called “CDK8 module” that performs physiological functions. CDK8 module and other protein catalytic subunits form the CDK8 mediator complex, which serves as a bridge between RNA polymerase II (RNA Pol II) and transcription factors, chromatin modifiers, promoters and enhancers to play a role in the transcription process. Evidence suggests that CDK8 may act as both a positive and negative regulator of transcription [8].

More and more research results indicate that CDK8 is an important tumor biomarker and has become an effective therapeutic target for cancer therapy. Therefore, in the past few years, a number of effective CDK8 inhibitors have emerged. This review described the biological functions of CDK8, particularly in carcinogenesis, summarized the interactions between representative CDK8 inhibitors and CDK8, and pointed out the basic principles for CDK8 inhibitor design based on the target.

In addition, three subunits of the kinase complex, i.e. CDK8, MED12, and MED13, have undergone independent gene duplications in vertebrates to produce paralogs CDK19, MED12L, and MED13L. CDK8 shares an 83% sequence identity with CDK19, while MED12 and MED13 share only a 59% and 53% sequence homology with their paralogues [9]. They have some overlapping as well diverse biological functions. For example, CDK8 or CDK19 was able to restore the growth of AML cells that had been inhibited. Studies also indicated their different roles in pharmacological inhibition and gene functions. CDK8 was ubiquitously expressed whereas CDK19 expression was tissue-specific. Knockdown of CDK8 in HCT116 showed a more severe effect than that of CDK19 [10]. Recent research results indicate that CDK8 and CDK19 regulate different gene sets through different mechanisms. CDK8-dependent regulation requires its kinase activity, while CDK19 governs the IFN-γ response through its scaffold function. In addition, when the function of CDK8/19 in normal cells is suppressed, the transcription function is not affected. At present, it may be difficult to generate CDK8-specific drugs that do not affect CDK19, but if the challenge can be overcome, it would allow CDK19 to compensate for the inhibition of CDK8 in the surrounding healthy tissue while eliminating cancer cells, which seem to depend specifically on CDK8.

Section snippets

Structural characteristics of CDK8

CDK8 exhibits a typical bilayer kinase folding structure. It is composed of N- leaves (residues 1–96) and C-leaves (residues 97–356). Active site residues are present in both regions. The two regions are connected by a hinged region consisting of amino acid residues Asp 98, Thr 99, Ala 100, and Gln 101 [11], [12]. The catalytic break is adjacent to the hinge region and lies between two regions, both of which contain active site residues. The C-terminal domain of the ATP binding site contains a

Dysregulation of CDK8 in human cancers

Abnormal expression of CDK8 has been observed in various malignant tumors [42], [43], [44], [45], [46]. The following sections detail the role of CDK8 in colorectal cancer, breast cancer, melanoma, and prostate cancer, and highlight that CDK8 may be a promising therapeutic target [39], [47], [48], [49], [50], [51].

Structure – activity relationship of natural product and its derivatives

In 2006, scientists isolated a class of abeo-9(10–19)-androstane type sternal alkaloids from the Indonesian marine sponge Corticium simplex, which contains 11 natural products that share a common core skeleton [110]. Corticium simplex extracts exerted antiproliferative effects against human umbilical vein endothelial cells (HUVECs). Further studies showed that the isoquinoline structure was very important for the activity and selectivity of these extracts, and compounds that did not contain the

Summary of amino acid residues and typical structural characteristics

Through analysis of SAR of the above compounds and the interactions between these compounds and their target, we can find that the typical type I and type II CDK8 inhibitors combined with pocket way of being has obvious differences, different type I CDK8 inhibitors undergo common interactions with the CDK8 kinase binding pocket. To better understand CDK8 binding patterns, we classified the effective binding regions as follows:

Deep pocket region: This region comprises several amino acid residues

Methods of discovering new CDK8 inhibitors

Based on the understanding of CDK8 kinase targets and existing small molecular inhibitors, we propose several rapid and efficient methods to find new CDK8 small molecular inhibitors.

Fragment-based drug design: The hinge area of CDK8 is critical to its function [94], [95]. Through screening of pharmacophores, we can identify fragments that effectively interact with the hinge region. We can then find molecular fragments that interact with the front pocket and the DMG-surrounding area. Then,

Future directions

Cyclin-dependent kinase 8 is a member of the CDK family and is involved in regulation of multiple signaling pathways. In addition, CDK8 is important in cancer cell growth and proliferation. Inhibitors of CDK8 can have diverse structures. At present, development of CDK8 inhibitors is a relatively new endeavor [108]. Few CDK8 inhibitors have been reported and these compounds are typically non-selective. However, with the increasing understanding of CDK8, additional small molecule inhibitors may

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

The authors wish to thank the National Natural Science Foundation of China (No. 21977001, 21572003).

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