GSK6853, a Chemical Probe for Inhibition of the BRPF1 Bromodomain

Bamborough, Paul; Barnett, Heather; Becher, Isabelle; Bird, Mark J.; Chung, Chun‐wa; Craggs, Peter D.; Demont, Emmanuel H.; Diallo, Hawa; Fallon, David J.; Gordon, Laurie J.; Grandi, Paola; Hobbs, Clare I.; Hooper‐Greenhill, Edward; Jones, Emma; Law, Robert P.; Gall, Armelle Le; Lugo, David; Michon, Anne-Marie; Mitchell, Darren J.; Prinjha, Rab K.; Sheppard, Robert J.; Watson, Allan J. B.; Watson, Robert J.

doi:10.1021/acsmedchemlett.6b00092

Cited by 57 publications

(41 citation statements)

References 24 publications

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“…One of the more recent additions to the BRPF1/2/3 chemical probe tool box is GSK6853 ( 45 ), a potent and highly selective BRPF1 bromodomain inhibitor optimized from the previously reported GSK5959 ( 44 ) (Figure a) . In optimizing 44 to 45 , GSK improved the solubility from 8 μg mL −1 to 140 μg mL −1 , and consequently improved its applicability to in vivo experiments . This was achieved through the introduction of a basic nitrogen at the 4‐position of the piperidine ring, improving the compounds physicochemical properties whilst in turn forming a hydrogen bond to Asn651 carbonyl group to maintain potency, as predicted by X‐ray crystallography (Figure e).…”

Section: Typical Non‐bet Bromodomain Inhibitorsmentioning

confidence: 99%

“…[69] In optimizing 44 to 45, GSK improved the solubility from 8 mgmL À1 to 140 mgmL À1 , and consequently improvedi ts applicability to in vivo experiments. [70,71] This was achieved through the introduction of a basic nitrogen at the 4-position of the piperidine ring, improving the compounds physicochemical properties whilst in turn forming ah ydrogen bond to Asn651 carbonylg roup to maintain potency,a sp redicted by X-ray crystallography (Figure 9e). Further interrogationo ft he crystal structure presented the 2positiono ft he piperidine ring as av ector towardP ro658, one of only af ew residues not conserved between the BRPF family, where af avorable interaction with am ethyl group was harnessedfor improved BRPF1 potency(pIC 50 = 8.1) and BRPF subfamily selectivity (BRPF2 = 1000 and BRPF3 > 1000).…”

Section: Brpf1/2/3mentioning

confidence: 99%

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Advancements in the Development of non‐BET Bromodomain Chemical Probes

et al. 2019

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The bromodomain and extra terminal (BET) family of bromodomain‐containing proteins (BCPs) have been the subject of extensive research over the past decade, resulting in a plethora of high‐quality chemical probes for their tandem bromodomains. In turn, these chemical probes have helped reveal the profound biological role of the BET bromodomains and their role in disease, ultimately leading to a number of molecules in active clinical development. However, the BET subfamily represents just 8/61 of the known human bromodomains, and attention has now expanded to the biological role of the remaining 53 non‐BET bromodomains. Rapid growth of this research area has been accompanied by a greater understanding of the requirements for an effective bromodomain chemical probe and has led to a number of new non‐BET bromodomain chemical probes being developed. Advances since December 2015 are discussed, highlighting the strengths/caveats of each molecule, and the value they add toward validating the non‐BET bromodomains as tractable therapeutic targets.

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Section: Typical Non‐bet Bromodomain Inhibitorsmentioning

confidence: 99%

Section: Brpf1/2/3mentioning

confidence: 99%

Advancements in the Development of non‐BET Bromodomain Chemical Probes

et al. 2019

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“…For example, the chemical probes (+)-JQ1 (BRD4), A395 (EED), T-26c (MMP-13), and GSK-6853 (BRPF1) are all ALARM NMR-negative (Figure 5) (Bamborough et al, 2016; Filippakopoulos et al, 2010; He et al, 2017; Nara et al, 2014). …”

Section: Commentarymentioning

confidence: 99%

ALARM NMR for HTS Triage and Chemical Probe Validation

Dahlin

Cuellar

Singh

et al. 2018

CP Chemical Biology

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Nonspecific target engagement by test compounds and purported chemical probes is a significant source of assay interference and promiscuous bioactivity in high-throughput screening (HTS) and chemical biology. Most counter-screens for thiol-reactive compounds utilize mass spectrometry or fluorescence detection, and non-proteinaceous reporters like glutathione that may not always approximate the reactivity of protein side-chains. By contrast, a La assay to detect reactive molecules by nuclear magnetic resonance (ALARM NMR) is an industry-developed protein-based [H-C]-heteronuclear multiple quantum coherence (HMQC) NMR counter-screen to identify nonspecific protein interactions by test compounds by reporting their tendencies to modulate the human La antigen conformation. This is a users-guide to the production of theC-labeled La antigen reporter protein, the reaction of test compounds with this reporter protein, as well as the collection and analysis of characteristic NMR spectra. Combined with other assay interference counter-screens, this assay will enhance chemical biology by helping researchers better prioritize chemical matter and which will increase the number of tractable HTS screening actives and aid in the development of better chemical probes.

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“…A benzimidazolone GSK6853 was reported as a potent (pIC 50 = 8.1), soluble, cell active, and highly selective (>1600-fold in BROMO scan ) inhibitor of the BRPF1 BrD, and revealed properties suitable for in vivo studies. [37]…”

Section: Chemical Modulators For Acetyl-lysine Binding Domainsmentioning

confidence: 99%

Chemical modulators for epigenome reader domains as emerging epigenetic therapies for cancer and inflammation

Zaware

Zhou

2017

Current Opinion in Chemical Biology

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Site-specific lysine acetylation and methylation on histones are critical post-translational modifications (PTMs) that govern ordered gene transcription in chromatin. Mis-regulation of these histone PTM-mediated processes has been shown to be associated with human diseases. Since the 2010 landmark reports of small molecules (+)-JQ1 and I-BET762 that target the acetyl-lysine ‘reader’ Bromodomain and Extra Terminal domain (BET) proteins, there have been relentless efforts to develop epigenetic therapy with small molecules to modulate molecular interactions of epigenome reader domain proteins with PTMs. In addition to BET, the other emerging targets include non-BET acetyl- and methyl-lysine reader domains. This review covers the key chemical modulators of the aforementioned epigenome reader proteins.

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GSK6853, a Chemical Probe for Inhibition of the BRPF1 Bromodomain

Cited by 57 publications

References 24 publications

Advancements in the Development of non‐BET Bromodomain Chemical Probes

Advancements in the Development of non‐BET Bromodomain Chemical Probes

ALARM NMR for HTS Triage and Chemical Probe Validation

Chemical modulators for epigenome reader domains as emerging epigenetic therapies for cancer and inflammation

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