Elsevier

Drug Discovery Today

Volume 11, Issues 3–4, February 2006, Pages 97-109
Drug Discovery Today

Review
Keynote review: Chromatin control and cancer-drug discovery: realizing the promise

https://doi.org/10.1016/S1359-6446(05)03691-3Get rights and content

Recent years have seen major advances in elucidating the complexity of chromatin and its role as an epigenetic regulator of gene expression in eukaryotes. We now have a basic understanding of chromatin control and the enzymatic modifications that impart diverse regulatory cues to the functional activity of the genome. Most importantly, although research into chromatin has uncovered fascinating insights into the control of gene expression, it has also generated a large body of information that is being harnessed to develop new therapeutic modalities for treating cancer. Here, we discuss recent advances that support the contention that future generations of chromatin-modulating drugs will provide a significant group of new, mechanism-based therapeutics for cancer.

Section snippets

HATs

It has been known for some time that the acetylation level of histones correlates with transcriptional activity [19, 20]. The ɛ -amino group of specific lysine residues in the tail region of the four core histones becomes acetylated. Originally, this was believed to loosen chromatin by neutralizing the positive charge of lysine and, thereby, facilitating transcription [21]. However, regulation of the higher-order folding of chromatin, together with subsequent influence on compaction and

HDACs

The acetylase activity of HATs is counter-balanced by the opposing deacetylase activity, which also plays a central role in controlling gene expression. In mammalian cells the HDAC family is divided into three classes (Table 2). Classes I and II are structurally similar, particularly across the active site and their enzyme activity is zinc-dependent [44]. By contrast, class III enzymes (known as the SIRT family because of their similarity with the yeast sirtuins) are zinc-independent and

Lysine methyltransferases

Histone tails can be mono-, di- and tri-methylated on the ɛ -amino group of lysine residues, and either mono- or di-methylated on arginine residues [67]. Most lysine methyltransferases are characterized by a conserved SET domain (Figure 2) and, from the cancer perspective, SET domain proteins are under abnormal control in tumours (Table 3) [68]. Depending on the context, lysine methylation provides either an activating or repressing modification [69]. Thus, tri-methylation of Lys9 in histone H3

Arginine methyltransferases

Protein arginine methyltransferases (PRMTs) catalyze the transfer of methyl groups to the guanidino nitrogen of arginine residues [93]. PRMTs are divided into two groups depending on whether they catalyze asymmetric or symmetric di-methylations. To date, the region required for catalytic activity and binding of S-adenosyl-l-methionine cofactor is similar in all PRMTs [94, 95], but only two, PRMT5 and PRMT7, catalyze symmetric dimethylation [94].

Currently, no mutations have been identified in

Phosphokinases

Phosphorylation of chromatin has an important role in mitosis and transcriptional control. The phosphorylation of Ser10 in H3 is associated with chromosome condensation during mitosis, and in interphase cells facilitate transcriptional activation in response to a host of different signalling events [112]. At least two groups of kinases are likely to be involved in regulating the phosphorylation of Ser10. These include aurora kinases, which are required for chromosome architecture and

Cancer-drug discovery

Drugs that regulate DNA methylation validate epigenetic control as an important mechanism in cancer and a viable therapeutic target [121, 122]. It has been known for some time that DNA methylation is abnormal in tumour cells [123] where hypermethylation of CpG islands prompts transcriptional silencing [62]. At least three methyltransferases, DNMT1, DNMT2 and DNMT3, lay down the pattern of genomic methylation [124] and, in cancer cells, there are many examples of tumour-suppressor genes that are

Concluding comments and future perspectives

We are embarking on a new era of cancer-drug discovery in which chromatin-regulating drugs are taking centre stage. Concerted efforts to develop HDAC inhibitors, together with the promising results from clinical trials, places HDAC inhibitors as strong contenders for the first class of chromatin drug to achieve clinical utility. Given the current interest in the other types of enzymes involved with chromatin control, it seems likely that HATs and MTases will also be tractable therapeutically

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    “We expect that the fever-pitch progress in chromatim drug discovery will yield new agents that provide improved, efficacious cancer drugs”

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    Adam Inche

    Adam Inche was a Chemistry undergraduate at St Andrews University. After graduating in 1998, he moved to York University to undertake an M.Res. in Biomolecular Science. Since 2002 he has pursued D.Phil. studies in Nick La Thangue's laboratory at the University of Oxford. His research focus has been towards understanding the role of chromatin-regulating enzymes in cell-division control, particularly cancer.

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    Nick La Thangue

    Nick La Thangue is Professor of Cancer Biology at the University of Oxford. He has extensive scientific and commercial experience from the biotechnology sector and a particular interest in developing drugs that target chromatin and cell-cycle control. He was the Founder of Prolifix, a successful spin-out from the Medical Research Council, focused on cancer drug discovery. Previously, he was the Cathcart Chair of Biochemistry at the University of Glasgow. He is also a Fellow of the Royal Society of Edinburgh and a Member of EMBO.

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