In vivo evaluation of a novel, orally bioavailable, small molecule growth hormone receptor antagonist

Rosengren, Linda; Parrow, Vendela; Chmielewska, Joanna; Mode, Agneta; Fhölenhag, Karin

doi:10.1016/j.ghir.2006.10.006

Cited by 7 publications

(2 citation statements)

References 33 publications

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“…In two studies, BVT-A suppressed GH induction of IGF1 expression in hepatocytes in vitro and reduced GH stimulation of IGF1 secretion and body weight in hypophysectomized rats. 138,139 However, it is unclear where in the GH signaling pathway this compound acts, and no subsequent activity has been reported in this area since the original publication.…”

Section: Strategies That Target Ghr Signalingmentioning

confidence: 99%

Targeting growth hormone function: strategies and therapeutic applications

Flanagan

Langley

et al. 2019

Sig Transduct Target Ther

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Human growth hormone (GH) is a classical pituitary endocrine hormone that is essential for normal postnatal growth and has pleiotropic effects across multiple physiological systems. GH is also expressed in extrapituitary tissues and has localized autocrine/paracrine effects at these sites. In adults, hypersecretion of GH causes acromegaly, and strategies that block the release of GH or that inhibit GH receptor (GHR) activation are the primary forms of medical therapy for this disease. Overproduction of GH has also been linked to cancer and the microvascular complications that are associated with diabetes. However, studies to investigate the therapeutic potential of GHR antagonism in these diseases have been limited, most likely due to difficulty in accessing therapeutic tools to study the pharmacology of the receptor in vivo. This review will discuss current and emerging strategies for antagonizing GH function and the potential disease indications.

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Section: Strategies That Target Ghr Signalingmentioning

confidence: 99%

Targeting growth hormone function: strategies and therapeutic applications

Flanagan

Langley

et al. 2019

Sig Transduct Target Ther

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“…The small molecular weight compound down-regulates GH-stimulated IGF-I expression [49]. Administration of BVT-A suppresses serum IGF-I, hepatic mRNA levels of IGF-I, IGF-BP3, ALS, and the IGF-I and GH receptors in hypophysectomized rats [50].…”

Section: Development Of Ghr Antagonistsmentioning

confidence: 99%

Growth hormone receptor modulators

Birzniece

Sata

2008

Rev Endocr Metab Disord

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Growth hormone (GH) regulates somatic growth, substrate metabolism and body composition. Its actions are elaborated through the GH receptor (GHR). GHR signalling involves the role of at least three major pathways, STATs, MAPK, and PI3-kinase/Akt. GH receptor function can be modulated by changes to the ligand, to the receptor or by factors regulating signal transduction. Insights on the physico-chemical basis of the binding of GH to its receptor and the stoichiometry required for activation of the GH receptor-dimer has led to the development of novel GH agonists and antagonists. Owing to the fact that GH has short half-life, several approaches have been taken to create long-acting GHR agonists. This includes the pegylation, sustained release formulations, and ligand-receptor fusion proteins. Pegylation of a GH analogue (pegvisomant) which binds but not activate signal transduction forms the basis of a new successful approach to the treatment of acromegaly. GH receptors can be regulated at a number of levels, by modifying receptor expression, surface availability and signalling. Insulin, thyroid hormones and sex hormones are among hormones that modulate GHR through some of these mechanisms. Estrogens inhibit GH signalling by stimulating the expression of SOCS proteins which are negative regulators of cytokine receptor signalling. This review of GHR modulators will cover the effects of ligand modification, and of factors regulating receptor expression and signalling.

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