3,5-Dimethylisoxazoles Act As Acetyl-lysine-mimetic Bromodomain Ligands

Hewings, David S.; Wang, Minghua; Philpott, Martin; Fedorov, O.; Uttarkar, Sagar; Filippakopoulos, P.; Picaud, S.; Vuppusetty, Chaitanya; Marsden, Brian D.; Knapp, Stefan; Conway, Stuart J.; Heightman, Tom D.

doi:10.1021/jm200640v

Cited by 216 publications

(249 citation statements)

References 42 publications

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“…The research focused on inhibition of BDs has been stimulated by the discovery of two potent compounds (I-BET762 and JQ1) with in vivo efficacy in murine models of NUT (nuclear protein in testis) midline carcinoma, as well as AML and severe immune inflammation [347][348][349][350]. Other recent works show the application of fragment-based drug discovery techniques for the identification of new BD inhibitors [316,347,348,351,352] in addition to evidence that the pharmacological inhibition of BET (bromodomains and extra terminal domain) family proteins leads to rapid and potent abrogation of MYC gene transcription [353].…”

Section: Rtt109mentioning

confidence: 99%

Modulation of Epigenetic Targets for Anticancer Therapy: Clinicopathological Relevance, Structural Data and Drug Discovery Perspectives

Andreoli¹,

Barbosa²,

Parenti³

et al. 2012

CPD

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Abstract:Research on cancer epigenetics has flourished in the last decade. Nevertheless growing evidence point on the importance to understand the mechanisms by which epigenetic changes regulate the genesis and progression of cancer growth. Several epigenetic targets have been discovered and are currently under validation for new anticancer therapies. Drug discovery approaches aiming to target these epigenetic enzymes with small-molecules inhibitors have produced the first pre-clinical and clinical outcomes and many other compounds are now entering the pipeline as new candidate epidrugs. The most studied targets can be ascribed to histone deacetylases and DNA methyltransferases, although several other classes of enzymes are able to operate post-translational modifications to histone tails are also likely to represent new frontiers for therapeutic interventions. By acknowledging that the field of cancer epigenetics is evolving with an impressive rate of new findings, with this review we aim to provide a current overview of pre-clinical applications of smallmolecules for cancer pathologies, combining them with the current knowledge of epigenetic targets in terms of available structural data and drug design perspectives.Keywords: Epigenetics, anticancer therapy, DNA methyltransferases, protein methyltransferases, demethylases, deacetylases, acetyltransferases, histone post-translational modifications, drug design, crystallography, small-molecule inhibitors. INTRODUCTIONThe term epigenetics currently refers to the mechanisms of temporal and spatial control of gene activity that do not depend on the DNA sequence, influencing the physiological and pathological development of an organism. The molecular mechanisms by which epigenetic changes occur are complex and cover a wide range of processes including paramutation, bookmarking, imprinting, gene silencing, carcinogenesis progression, and, most importantly, regulation of heterochromatin and histone modifications [1]. At a biochemical level, epigenetic alterations in chromatin involve methylation of DNA patterns, several forms of histone modifications and microRNA (miRNA) expression. All these processes modulate the structure of chromatin leading to the activation or silencing of gene expression [2][3][4][5][6]. More specifically, the chromatin remodeling is accomplished by two main mechanisms that concern the methylation of cytosine residues in DNA and a variety of post-translational modifications (PTMs) occurring at the N-terminal tails of histone proteins. These PTMs include acetylation, methylation, phosphorylation, ubiquitylation, sumoylation, glycosylation, ADPribosylation, carbonylation, citrullination and biotinylation [7,8]. Among all PTMs for example, histone tails can have its lysine residues acetylated, methylated or ubiquitilated; arginine can be methylated; serine and threonine residues can be phosphorylated [9][10][11][12][13][14][15][16][17]. These covalent modifications are able to cause other PTMs and the ensemble of this cross-talk is known as the his...

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Section: Rtt109mentioning

confidence: 99%

Modulation of Epigenetic Targets for Anticancer Therapy: Clinicopathological Relevance, Structural Data and Drug Discovery Perspectives

Andreoli¹,

Barbosa²,

Parenti³

et al. 2012

CPD

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“…The promising effects of BET inhibitors observed in cancer cell lines have stimulated the rapid optimization of these tool molecules to yield clinical candidate drugs (2). A number of weak inhibitors, such as ischemin (K D = 25 μM), have been reported to target the CBP/p300 bromodomain (14). The synthesis and binding modes of more potent CBP and BET/CBP inhibitors have been reported in the last year (15,16).…”

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confidence: 99%

CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses

Hammitzsch

Tallant

Fedorov

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Th17 responses are critical to a variety of human autoimmune diseases, and therapeutic targeting with monoclonal antibodies against IL-17 and IL-23 has shown considerable promise. Here, we report data to support selective bromodomain blockade of the transcriptional coactivators CBP (CREB binding protein) and p300 as an alternative approach to inhibit human Th17 responses. We show that CBP30 has marked molecular specificity for the bromodomains of CBP and p300, compared with 43 other bromodomains. In unbiased cellular testing on a diverse panel of cultured primary human cells, CBP30 reduced immune cell production of IL-17A and other proinflammatory cytokines. CBP30 also inhibited IL-17A secretion by Th17 cells from healthy donors and patients with ankylosing spondylitis and psoriatic arthritis. Transcriptional profiling of human T cells after CBP30 treatment showed a much more restricted effect on gene expression than that observed with the pan-BET (bromo and extraterminal domain protein family) bromodomain inhibitor JQ1. This selective targeting of the CBP/p300 bromodomain by CBP30 will potentially lead to fewer side effects than with the broadly acting epigenetic inhibitors currently in clinical trials.CBP/p300 | bromodomain | epigenetic inhibitors | Th17 | ankylosing spondylitis

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“…Together with important contributions from multiple academic laboratories [42][43][44][45], several BET selective chemical probes have provided an indication of the role of the CREBBP and EP300 bromodomains in human disease (Figure 2b). SGC-CBP30 (10) was developed through a collaboration between the SGC and the University of Oxford starting from unselective fragment 9 [46,47].…”

Section: Crebbp and Ep300mentioning

confidence: 99%

Clinical progress and pharmacology of small molecule bromodomain inhibitors

Theodoulou¹,

Tomkinson

Prinjha

et al. 2016

Current Opinion in Chemical Biology

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Bromodomains have emerged as an exciting target class for drug discovery over the past decade. Research has primarily focused on the bromodomain and extra terminal (BET) family of bromodomains, which has led to the development of multiple small molecule inhibitors and an increasing number of clinical assets. The excitement centred on the clinical potential of BET inhibition has stimulated intense interest in the broader family and the growing number of non-BET bromodomain chemical probes has facilitated phenotypic investigations, implicating these targets in a variety of disease pathways including cancer, inflammation, embryonic development and neurological disorders.

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3,5-Dimethylisoxazoles Act As Acetyl-lysine-mimetic Bromodomain Ligands

Cited by 216 publications

References 42 publications

Modulation of Epigenetic Targets for Anticancer Therapy: Clinicopathological Relevance, Structural Data and Drug Discovery Perspectives

Modulation of Epigenetic Targets for Anticancer Therapy: Clinicopathological Relevance, Structural Data and Drug Discovery Perspectives

CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses

Clinical progress and pharmacology of small molecule bromodomain inhibitors

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