Abstract
The follicle-stimulating hormone receptor (FSHR) has been targeted therapeutically for decades, due to its pivotal role in reproduction. To date, only purified and recombinant/biosimilar FSH have been used to target FSHR in assisted reproduction, with the exception of corifollitropin alfa; a modified gonadotropin in which the FSH beta subunit is joined to the C-terminal peptide of the human choriogonadotropin beta subunit, to extend serum half-life. Assisted reproduction protocols usually entail the trauma of multiple injections of FSH to initiate and promote folliculogenesis, which has prompted the development of a number of orally-available low molecular weight (LMW) chemical scaffolds targeting the FSHR. Furthermore, the recently documented roles of the FSHR in diverse extragonadal tissues, including cancer, fat metabolism, and bone density regulation, has highlighted the potential utility of LMW modulators of FSHR activity. Despite these chemical scaffolds encompassing a spectrum of in vitro and in vivo activities and pharmacological profiles, none have yet reached the clinic. In this review we discuss the major chemical classes of LMW molecules targeting the FSHR, and document their activity profiles and current status of development, in addition to discussing potential clinical applications.
Highlights
The hypothalamic-pituitary-gonadal axis comprises hypothalamic kisspeptin and neurokinin B (NKB) driving the secretion of gonadotropin-releasing hormone (GnRH)
Suramin has been tested in patients with refractory cancers including prostate cancer. In these patients decreases in plasma testosterone, follicle stimulating hormone (FSH) and prostate specific antigen have been observed [50, 51], and while overall survival rates were unchanged between placebo and suramin treatment groups, there were suggested palliative benefits with reduced pain, and opioid analgesic uptake [51]
These observations have led to increased interest in suramin within the arena of G protein-coupled receptor (GPCR) drug development, and despite poor oral uptake, have propagated interest in sulfonic acid containing low molecular weight (LMW) compounds as possible modulators of follicle-stimulating hormone receptor (FSHR) activity
Summary
The hypothalamic-pituitary-gonadal axis comprises hypothalamic kisspeptin and neurokinin B (NKB) driving the secretion of gonadotropin-releasing hormone (GnRH). The gonadotropins are large dimeric proteins that contact the gonadotropin receptors via multiple residues that include the glycan moieties, in addition to having a complex mechanism of receptor activation that includes structural movements within the extracellular domain (ECD) and the transmembrane (TM) domains of the receptor As a result, it appeared that a LMW molecule might not fulfill the requirements of both receptor binding and activation. Despite considerable progress in the development of LMW FSH analogs, none have yet entered the clinic In many cases, this is a result of in vitro activity failing to translate into in vivo activity, off-target effects/toxicity, synthesis issues, and frequently termination of research programs following pharmaceutical company acquisitions, and differing priorities of the acquiring company. We review the progress that has been made in developing LMW orally active FSHR analogs, and discuss their potential clinical applications
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