RVX-297- a novel BD2 selective inhibitor of BET bromodomains

Kharenko, Olesya A.; Gesner, Emily M.; Patel, Reena G.; Norek, Karen; White, André; Fontano, Eric; Suto, R.K.; Young, Peter R.; McLure, Kevin G.; Hansen, Henrik C.

doi:10.1016/j.bbrc.2016.06.021

Cited by 47 publications

(53 citation statements)

References 11 publications

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“…Whereas most BETis in development have similar affinity for both (i.e., pan) BET protein BDs, RVX-297 is a novel, orally bioavailable BETi with selectivity for BD2 (Kharenko et al, 2016). Apabetalone is another BD2-selective BETi currently in clinical trials for cardiovascular disease (McLure et al, 2013); the antiinflammatory properties of apabetalone have been demonstrated in a mouse model of atherosclerosis (Jahagirdar et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…RVX-297 is a novel, orally bioavailable BETi that has a 47-to 58-fold greater affinity for BD2 than for BD1 in the BET family of proteins (Kharenko et al, 2016). In this report, we characterize the anti-inflammatory properties of RVX-297 and demonstrate for the first time that a BD2-selective BETi impacts gene expression and cellular function in immune cell types that are involved in inflammation and autoimmunity, including macrophages, T cells, B cells, and synovial fibroblasts.…”

Section: Introductionmentioning

confidence: 99%

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RVX-297, a BET Bromodomain Inhibitor, Has Therapeutic Effects in Preclinical Models of Acute Inflammation and Autoimmune Disease

Jahagirdar

Attwell²,

Marušić³

et al. 2017

Mol Pharmacol

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Bromodomain (BD) and extra-terminal domain containing proteins (BET) are chromatin adapters that bind acetylated histone marks via two tandem BDs, BD1 and BD2, to regulate gene transcription. BET proteins are involved in transcriptional reprogramming in response to inflammatory stimuli. BET BD inhibitors (BETis) that are nonselective for BD1 or BD2 have recognized anti-inflammatory properties in vitro and counter pathology in models of inflammation or autoimmune disease. Although both BD1 and BD2 bind acetylated histone residues, they may independently regulate the expression of BET-sensitive genes. Here we characterized the ability of RVX-297, a novel orally active BETi with selectivity for BD2, to modulate inflammatory processes in vitro, in vivo, and ex vivo. RVX-297 suppressed inflammatory gene expression in multiple immune cell types in culture. Mechanistically, RVX-297 displaced BET proteins from the promoters of sensitive genes and disrupted recruitment of active RNA polymerase II, a property shared with pan-BETis that nonselectively bind BET BDs. In the lipopolysaccharide model of inflammation, RVX-297 reduced proinflammatory mediators assessed in splenic gene expression and serum proteins. RVX-297 also countered pathology in three rodent models of polyarthritis: rat and mouse collagen-induced arthritis, and mouse collagen antibody-induced arthritis. Further, RVX-297 prevented murine experimental autoimmune encephalomyelitis (a model of human multiple sclerosis) disease development when administered prophylactically and reduced hallmarks of pathology when administered therapeutically. We show for the first time that a BD2-selective BETi maintains anti-inflammatory properties and is effective in preclinical models of acute inflammation and autoimmunity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

RVX-297, a BET Bromodomain Inhibitor, Has Therapeutic Effects in Preclinical Models of Acute Inflammation and Autoimmune Disease

Jahagirdar

Attwell²,

Marušić³

et al. 2017

Mol Pharmacol

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“…This includes; multiple pan inhibitors, some of which have entered clinical trials (see below); BD1 selective inhibitors, such as MS-436, Olinone and BI-2536, as well as the BD2 selective inhibitors RVX-208 and RVX-297 (Steegmaier et al 2007; Park et al 2013; Picaud et al 2013; Zhang et al 2013; McLure et al 2014; Kharenko et al 2016). As expected, inhibition of individual BET bromodomains will lead to different transcriptional and phenotypic outcomes.…”

Section: Small-molecule Inhibitors Of Bet Bromodomainsmentioning

confidence: 99%

Targeting Cancer Cells with BET Bromodomain Inhibitors

Vakoc

2017

Cold Spring Harb Perspect Med

161

126

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Cancer cells are often hypersensitive to the targeting of transcriptional regulators, which may reflect the deregulated gene expression program that underlies malignant transformation. One of the most prominent transcriptional vulnerabilities in human cancer to emerge in recent years is the bromodomain and extraterminal (BET) family of proteins, which are coactivators that link acetylated transcription factors and histones to the activation of RNA polymerase II. Despite unclear mechanisms underlying the gene-specificity of BET protein function, small-molecules targeting these regulators will preferentially suppress transcription of cancer-promoting genes. As a consequence, BET inhibitors elicit anti-cancer activity in numerous malignant contexts at doses that can be tolerated by normal tissues, a finding supported by animal studies and by phase I clinical trials in human cancer patients. In this chapter, we will discuss the remarkable, and often perplexing, therapeutic effects of BET bromodomain inhibition in cancer.

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“…7B ). Recently, RVX-297, a RVX-208 analog and BET-BrD2 selective (K d of 1.44 μM for BRD4-BrD1 and K d of 0.18 μM for BRD4-BrD2), has been reported [41] to exhibit both different pharmacodynamic profile and biological activity as demonstrated in mouse models for autoimmune disease of multiple sclerosis and arthritis [42,43]. …”

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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RVX-297- a novel BD2 selective inhibitor of BET bromodomains

Cited by 47 publications

References 11 publications

RVX-297, a BET Bromodomain Inhibitor, Has Therapeutic Effects in Preclinical Models of Acute Inflammation and Autoimmune Disease

RVX-297, a BET Bromodomain Inhibitor, Has Therapeutic Effects in Preclinical Models of Acute Inflammation and Autoimmune Disease

Targeting Cancer Cells with BET Bromodomain Inhibitors

Structural features and inhibitors of bromodomains

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