Fragment-Based Design of Selective Nanomolar Ligands of the CREBBP Bromodomain

Unzue, Andrea; Xu, Ming; Dong, Jing; Wiedmer, L.; Spiliotopoulos, Dimitrios; Caflisch, Amedeo; Nevado, Cristina

doi:10.1021/acs.jmedchem.5b00172

Cited by 56 publications

(56 citation statements)

References 39 publications

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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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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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“…Two out of the 17 selected hits inhibited the interaction between AcK peptide and CREBBP bromodomain at low µM range. Guided by extensive MD simulations and high resolution X-ray crystallography, they optimized both active fragment hits into nanomolar inhibitors of CREBBP bromodomain [42,58].…”

Section: Citationmentioning

confidence: 99%

Using Fragment Based Drug Discovery to Target Epigenetic Regulators in Cancer

Young

Chang

2017

MOJBB

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Cancer is associated with epigenetic changes such as abnormal DNA methylation and histone tail modifications, and these changes result in tumor suppressor gene silencing, oncogene overexpression, and genome instability -phenomena that are closely linked to cancer development. The epigenetic marks on DNA and histones are reversible and therefore it is possible to restore normal patterns through chemically targeting epigenetic regulators that generate, maintain, recognize, and remove these marks. In recent years, fragment-based drug discovery (FBDD) has been used to target both the protein-protein interactions (PPI) as well as the enzymatic functions of epigenetic factors. Low molecular weight fragments (MW<300) efficiently sample chemical space and can bind to discreet binding pockets on target proteins such as those found on PPI interface. In this review, we describe the biophysical, biochemical, and in silico methods used for FBDD. We also discuss the examples of using FBDD to target epigenetic readers such as bromodomain-containing proteins and epigenetic enzymes such as arginine methyltransferases 6 (PRMT6), lysine demethylase 4 (KDM4), and Sirtuin 2 (SIRT2). FBDD provides an economical alternative to traditional high throughput screening. Effective FBDD endeavors depend heavily on gaining structural information of ligand-protein interactions early on and the close collaboration between biophysicists, chemists, and biologists in all stages of the drug discovery process. Using FBDD, protein-protein interactions in non-enzymatic epigenetic factors can potentially be chemically modulated. Furthermore, FBDD enables the identification of new binding pockets that can improve compound specificity against various epigenetic enzymes.

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“…Another acetophenone-based ligand, named UL04 ( Fig. 8C ) was discovered by virtual screening and optimized using molecular dynamics[48,49]. The ligand is potent for CBP-BrD (K d = 0.77 μM) and displays a 65-fold greater affinity for this BrD than BRD4-BrD1.…”

Section: Small-molecule Inhibitors Of Brdsmentioning

confidence: 99%

Structural features and inhibitors of bromodomains

Meslamani

Smith

Sánchez

et al. 2016

Drug Discovery Today: Technologies

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Bromodomains are conserved structural modules responsible for recognizing acetylated-lysine residues on histone tails and other transcription-associated proteins, such as transcription factors and co-factors. Owing to their important functions in the regulation of ordered gene transcription in chromatin, bromodomains of the BET family proteins have recently been shown as druggable targets for a wide array of human diseases, including cancer and inflammation. Here we review the structural and functional features of the bromodomains and their small-molecule inhibitors. Additional new insights provided herein highlight the landscape of the ligand binding sites in the bromodomains that will hopefully facilitate further development of new inhibitors with optimal affinity and selectivity.

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Fragment-Based Design of Selective Nanomolar Ligands of the CREBBP Bromodomain

Cited by 56 publications

References 39 publications

Clinical progress and pharmacology of small molecule bromodomain inhibitors

Clinical progress and pharmacology of small molecule bromodomain inhibitors

Using Fragment Based Drug Discovery to Target Epigenetic Regulators in Cancer

Structural features and inhibitors of bromodomains

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