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通过抑制生长激素受体合成来调节 GH/IGF1 轴的小分子。

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

机构信息

Department of Cell Biology, Centre for Molecular Medicine, University Medical Center (UMC) Utrecht, Utrecht, Netherlands.

Specs Compound Handling, Zoetermeer, Netherlands.

出版信息

Front Endocrinol (Lausanne). 2022 Jul 28;13:926210. doi: 10.3389/fendo.2022.926210. eCollection 2022.

DOI:10.3389/fendo.2022.926210
PMID:35966052
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9365994/
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.

摘要

生长激素 (GH) 和胰岛素样生长因子-1 (IGF1) 在哺乳动物的发育、细胞增殖和寿命中起着重要作用。特别是在肿瘤生长的情况下，迫切需要控制 GH/IGF1 轴。在这项研究中，我们筛选了一个包含 38480 种化合物的文库，并在两轮类似物选择中，根据以下标准确定了活性先导化合物：抑制生长激素受体 (GHR) 及其下游效应子 Jak2 和 STAT5 的活性，以及抑制乳腺癌和结肠癌细胞的生长。最活跃的小分子 (BM001) 以 10-30 nM 的 IC50 抑制了人类癌细胞中的 GH/IGF1 轴和细胞增殖。BM001 耗尽了人淋巴母细胞中的 GHR。在临床前异种移植实验中，BM001 在移植了 MDA-MB-231 乳腺癌细胞的小鼠中显示出肿瘤体积的强烈下降。从机制上讲，该药物作用于 GHR 的合成。我们的研究结果为用小分子抑制 GH/IGF1 轴提供了可能性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f5a/9365994/4f651f6f5744/fendo-13-926210-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f5a/9365994/03443b20d19c/fendo-13-926210-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f5a/9365994/e15f6c7f2b8c/fendo-13-926210-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f5a/9365994/4dbd48206bc8/fendo-13-926210-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f5a/9365994/5e10e09c0836/fendo-13-926210-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f5a/9365994/923223ff8d27/fendo-13-926210-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f5a/9365994/faf346b3d9a1/fendo-13-926210-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f5a/9365994/4f651f6f5744/fendo-13-926210-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f5a/9365994/03443b20d19c/fendo-13-926210-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f5a/9365994/e15f6c7f2b8c/fendo-13-926210-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f5a/9365994/4dbd48206bc8/fendo-13-926210-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f5a/9365994/5e10e09c0836/fendo-13-926210-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f5a/9365994/923223ff8d27/fendo-13-926210-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f5a/9365994/faf346b3d9a1/fendo-13-926210-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f5a/9365994/4f651f6f5744/fendo-13-926210-g007.jpg

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