In vivo effects of AZD4547, a novel fibroblast growth factor receptor inhibitor, in a mouse model of endometriosis

Sara Santorelli, Deborah P Fischer, Deborah Fischer, Michael Harte, Michael K Harte, Johanna Laru, Kay Marshall, Kay M Marshall
Pharmacology research & perspectives · 2021 · vol. 9(2) , pp. e00759 · doi:10.1002/prp2.759 · PMID:33811484 · W3112347848
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AZD4547, a fibroblast growth factor receptor inhibitor, and etonogestrel reduced endometriotic lesion growth in mice, but only AZD4547 consistently avoided estrous cycle disruption.

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Abstract

Endometriosis is a chronic disease, characterized by the growth of endometrial-like cells outside the uterine cavity. Due to its complex pathophysiology, a totally resolving cure is yet to be found. The aim of this study was to compare the therapeutic efficacy of AZD4547, a novel fibroblast growth factor receptor inhibitor (FGFRI), with a well-characterized progestin, etonogestrel (ENG) using a validated in vivo mouse model of endometriosis. Endometriosis was induced by transplanting uterine fragments from donor mice in proestrus into the peritoneal cavity of recipient mice, which then developed into cyst-like lesions. AZD4547 and ENG were administered systemically either from the day of endometriosis induction or 2-weeks post-surgery. After 20 days of treatment, the lesions were harvested; their size and weight were measured and analyzed histologically or by qRT-PCR. Stage of estrous cycle was monitored throughout. Compared to vehicle, AZD4547 (25 mg/kg) was most effective in counteracting lesion growth when treating from day of surgery and 2 weeks after; ENG (0.8 mg/kg) was similarly effective in reducing lesion growth but only when administered from day of surgery. Each downregulated FGFR gene expression (p < 0.05). AZD4547 at all doses and ENG (0.008 mg/kg) caused no disturbance to the estrous cycle. ENG at 0.08 and 0.8 mg/kg was associated with partial or complete estrous cycle disruption and hyperemia of the uteri. AZD4547 and ENG both attenuated endometriotic lesion size, but only AZD4547 did not disrupt the estrous cycle, suggesting that targeting of FGFR is worthy of further investigation as a novel treatment for endometriosis.

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Condition tags

mesh:D004715endometriosis

MeSH descriptors

Benzamides Endometriosis Estrous Cycle Piperazines Pyrazoles Receptors, Fibroblast Growth Factor Animals Benzamides Benzamides Desogestrel Desogestrel Desogestrel Disease Models, Animal Drug Evaluation, Preclinical Endometriosis Endometriosis Endometrium Endometrium Endometrium Estrous Cycle

Citation neighborhood

Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

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Cited by (3)

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