Small molecules to regulate the GH/IGF1 axis by inhibiting the growth hormone receptor synthesis.

Autor:	van der Velden LM; Department of Cell Biology, Centre for Molecular Medicine, University Medical Center (UMC) Utrecht, Utrecht, Netherlands., Maas P; Specs Compound Handling, Zoetermeer, Netherlands., van Amersfoort M; Department of Pathology, University Medical Center (UMC) Utrecht, Utrecht, Netherlands., Timmermans-Sprang EPM; Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands., Mensinga A; Department of Cell Biology, Centre for Molecular Medicine, University Medical Center (UMC) Utrecht, Utrecht, Netherlands., van der Vaart E; Department of Cell Biology, Centre for Molecular Medicine, University Medical Center (UMC) Utrecht, Utrecht, Netherlands., Malergue F; Department of Research and Development, Beckman Coulter Life Science, Immunotech Marseille, Marseille, France., Viëtor H; Drug Discovery Factory (DDF) Ventures, Breukelen, Netherlands., Derksen PWB; Department of Pathology, University Medical Center (UMC) Utrecht, Utrecht, Netherlands., Klumperman J; Department of Cell Biology, Centre for Molecular Medicine, University Medical Center (UMC) Utrecht, Utrecht, Netherlands., van Agthoven A; Department of Research and Development, Beckman Coulter Life Science, Immunotech Marseille, Marseille, France., Egan DA; Cell Screening Core, Department of Cell Biology, Center for Molecular Medicine, University Medical Center, Utrecht, Netherlands., Mol JA; Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands., Strous GJ; Department of Cell Biology, Centre for Molecular Medicine, University Medical Center (UMC) Utrecht, Utrecht, Netherlands.
Jazyk:	angličtina
Zdroj:	Frontiers in endocrinology [Front Endocrinol (Lausanne)] 2022 Jul 28; Vol. 13, pp. 926210. Date of Electronic Publication: 2022 Jul 28 (Print Publication: 2022).
DOI:	10.3389/fendo.2022.926210
Abstrakt:	Growth hormone (GH) and insulin-like growth factor-1 (IGF1) play an important role in mammalian development, cell proliferation and lifespan. Especially in cases of tumor growth there is an urgent need to control the GH/IGF1 axis. In this study we screened a 38,480-compound library, and in two consecutive rounds of analogues selection, we identified active lead compounds based on the following criteria: inhibition the GH receptor (GHR) activity and its downstream effectors Jak2 and STAT5, and inhibition of growth of breast and colon cancer cells. The most active small molecule (BM001) inhibited both the GH/IGF1 axis and cell proliferation with an IC50 of 10-30 nM of human cancer cells. BM001 depleted GHR in human lymphoblasts. In preclinical xenografted experiments, BM001 showed a strong decrease in tumor volume in mice transplanted with MDA-MB-231 breast cancer cells. Mechanistically, the drug acts on the synthesis of the GHR. Our findings open the possibility to inhibit the GH/IGF1 axis with a small molecule. Competing Interests: Authors GS, PM and HV serve as scientific advisors and have equity in Bimini Biotech BV, a biotechnology company that seeks to exploit regulators of GH/IGF1 activity but does not provide financial support for the technology described in this paper. Author LV is employed by College ter Beoordeling van Geneesmiddelen. Author DE is employed by Core Life Analytics B.V. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 van der Velden, Maas, van Amersfoort, Timmermans-Sprang, Mensinga, van der Vaart, Malergue, Viëtor, Derksen, Klumperman, van Agthoven, Egan, Mol and Strous.)
Databáze:	MEDLINE
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