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A Strategy to Identify Compounds that Affect Cell Growth and Survival in Cultured Mammalian Cells at Low-to-Moderate Throughput
Published on: September 22, 2019
Small molecules to regulate the GH/IGF1 axis by inhibiting the growth hormone receptor synthesis
Lieke M van der Velden1, Peter Maas2, Miranda van Amersfoort3
1Department of Cell Biology, Centre for Molecular Medicine, University Medical Center (UMC) Utrecht, Utrecht, Netherlands.
Abstract:
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.
Insights
Researchers identified a small molecule, BM001, that effectively inhibits the growth hormone/insulin-like growth factor-1 (GH/IGF1) axis and cancer cell proliferation. This compound shows promise for controlling tumor growth by targeting the GH receptor (GHR).
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- The growth hormone (GH) and insulin-like growth factor-1 (IGF1) axis is crucial for mammalian development, cell proliferation, and lifespan.
- Dysregulation of the GH/IGF1 axis is implicated in tumor growth, necessitating targeted therapeutic strategies.
Purpose of the Study:
- To identify small molecules that inhibit the GH/IGF1 axis and suppress cancer cell proliferation.
- To evaluate the efficacy of lead compounds in preclinical cancer models.
Main Methods:
- Screening of a 38,480-compound library to identify inhibitors of GH receptor (GHR) activity, Jak2, and STAT5.
- Assessing the impact of lead compounds on breast and colon cancer cell growth.
- Preclinical evaluation of the most potent compound (BM001) in xenografted mice.
Main Results:
- BM001 inhibited the GH/IGF1 axis and cancer cell proliferation with IC50 values of 10-30 nM.
- BM001 treatment led to the depletion of GHR in human lymphoblasts.
- BM001 significantly reduced tumor volume in mice bearing MDA-MB-231 breast cancer xenografts.
Conclusions:
- BM001 is a potent small molecule inhibitor of the GH/IGF1 axis and cancer cell proliferation.
- The drug acts by modulating GHR synthesis, offering a novel therapeutic approach.
- Targeting the GH/IGF1 axis with small molecules presents a promising strategy for cancer treatment.
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