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

Lieke M van der Velden; Peter Maas; Miranda van Amersfoort; Elpetra P M Timmermans-Sprang; Anneloes Mensinga; Elisabeth van der Vaart; Fabrice Malergue; Henk Viëtor; Patrick W B Derksen; Judith Klumperman; Andreas van Agthoven; David A Egan; Jan A Mol; Ger J Strous

doi:10.3389/fendo.2022.926210

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

Lieke M van der Velden
, Peter Maas
, Miranda van Amersfoort
, Elpetra P M Timmermans-Sprang
, Anneloes Mensinga
, Elisabeth van der Vaart
, Fabrice Malergue
, Henk Viëtor
, Patrick W B Derksen
, Judith Klumperman
, Andreas van Agthoven
, David A Egan
, Jan A Mol
, Ger J Strous

University Medical Center Utrecht
Specs Compound Handling
Department Research and Development, Hycult Biotech, Uden, The Netherlands.
Drug Discovery Factory (DDF) Ventures

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	926210
Pages (from-to)	1-14
Journal	Frontiers in Endocrinology
Volume	13
DOIs	https://doi.org/10.3389/fendo.2022.926210
Publication status	Published - 28 Jul 2022

Bibliographical note

Funding Information:
This work was supported by the Dutch Technology Foundation Stichting Technische Wetenschappen (STW), which is the applied science division of the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO), and the Technology Program of the Ministry of Economic Affairs, Grant 11155: “Targeting the Jak2-GH receptor interaction for treatment of cancer”, by the European Network of Excellence, RUBICON “Role of ubiquitin and ubiquitin-like modifiers in cellular regulation” (Grant LSHG-CT-2005-018683); the Marie Curie Network, “UbiRegulators” (Grant MRTNCT-2006-034555), the Dutch Cancer Society (KWF-UU-2014-7201 and KWF-UU-2016-10456).

Publisher Copyright:
Copyright © 2022 van der Velden, Maas, van Amersfoort, Timmermans-Sprang, Mensinga, van der Vaart, Malergue, Viëtor, Derksen, Klumperman, van Agthoven, Egan, Mol and Strous.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

BM001
GH inhibitor
IGF1 inhibitor
autocrine
cancer
ribosomal synthesis

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fendo-13-926210Final published version, 3.31 MBLicence: CC BY

Cite this

van der Velden, L. M., Maas, P., van Amersfoort, M., Timmermans-Sprang, E. P. M., Mensinga, A., van der Vaart, E., Malergue, F., Viëtor, H., Derksen, P. W. B., Klumperman, J., van Agthoven, A., Egan, D. A., Mol, J. A., & Strous, G. J. (2022). Small molecules to regulate the GH/IGF1 axis by inhibiting the growth hormone receptor synthesis. Frontiers in Endocrinology, 13, 1-14. Article 926210. https://doi.org/10.3389/fendo.2022.926210

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title = "Small molecules to regulate the GH/IGF1 axis by inhibiting the growth hormone receptor synthesis",

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.",

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author = "\{van der Velden\}, \{Lieke M\} and Peter Maas and \{van Amersfoort\}, Miranda and Timmermans-Sprang, \{Elpetra P M\} and Anneloes Mensinga and \{van der Vaart\}, Elisabeth and Fabrice Malergue and Henk Vi{\"e}tor and Derksen, \{Patrick W B\} and Judith Klumperman and \{van Agthoven\}, Andreas and Egan, \{David A\} and Mol, \{Jan A\} and Strous, \{Ger J\}",

note = "Funding Information: This work was supported by the Dutch Technology Foundation Stichting Technische Wetenschappen (STW), which is the applied science division of the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO), and the Technology Program of the Ministry of Economic Affairs, Grant 11155: “Targeting the Jak2-GH receptor interaction for treatment of cancer”, by the European Network of Excellence, RUBICON “Role of ubiquitin and ubiquitin-like modifiers in cellular regulation” (Grant LSHG-CT-2005-018683); the Marie Curie Network, “UbiRegulators” (Grant MRTNCT-2006-034555), the Dutch Cancer Society (KWF-UU-2014-7201 and KWF-UU-2016-10456). Publisher Copyright: Copyright {\textcopyright} 2022 van der Velden, Maas, van Amersfoort, Timmermans-Sprang, Mensinga, van der Vaart, Malergue, Vi{\"e}tor, Derksen, Klumperman, van Agthoven, Egan, Mol and Strous.",

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doi = "10.3389/fendo.2022.926210",

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van der Velden, LM, Maas, P, van Amersfoort, M, Timmermans-Sprang, EPM, Mensinga, A, van der Vaart, E, Malergue, F, Viëtor, H, Derksen, PWB, Klumperman, J, van Agthoven, A, Egan, DA, Mol, JA & Strous, GJ 2022, 'Small molecules to regulate the GH/IGF1 axis by inhibiting the growth hormone receptor synthesis', Frontiers in Endocrinology, vol. 13, 926210, pp. 1-14. https://doi.org/10.3389/fendo.2022.926210

TY - JOUR

T1 - Small molecules to regulate the GH/IGF1 axis by inhibiting the growth hormone receptor synthesis

AU - van der Velden, Lieke M

AU - Maas, Peter

AU - van Amersfoort, Miranda

AU - Timmermans-Sprang, Elpetra P M

AU - Mensinga, Anneloes

AU - van der Vaart, Elisabeth

AU - Malergue, Fabrice

AU - Viëtor, Henk

AU - Derksen, Patrick W B

AU - Klumperman, Judith

AU - van Agthoven, Andreas

AU - Egan, David A

AU - Mol, Jan A

AU - Strous, Ger J

N1 - Funding Information: This work was supported by the Dutch Technology Foundation Stichting Technische Wetenschappen (STW), which is the applied science division of the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO), and the Technology Program of the Ministry of Economic Affairs, Grant 11155: “Targeting the Jak2-GH receptor interaction for treatment of cancer”, by the European Network of Excellence, RUBICON “Role of ubiquitin and ubiquitin-like modifiers in cellular regulation” (Grant LSHG-CT-2005-018683); the Marie Curie Network, “UbiRegulators” (Grant MRTNCT-2006-034555), the Dutch Cancer Society (KWF-UU-2014-7201 and KWF-UU-2016-10456). Publisher Copyright: Copyright © 2022 van der Velden, Maas, van Amersfoort, Timmermans-Sprang, Mensinga, van der Vaart, Malergue, Viëtor, Derksen, Klumperman, van Agthoven, Egan, Mol and Strous.

PY - 2022/7/28

Y1 - 2022/7/28

N2 - 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.

AB - 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.

KW - BM001

KW - GH inhibitor

KW - IGF1 inhibitor

KW - autocrine

KW - cancer

KW - ribosomal synthesis

UR - https://www.scopus.com/pages/publications/85135829297

U2 - 10.3389/fendo.2022.926210

DO - 10.3389/fendo.2022.926210

M3 - Article

C2 - 35966052

SN - 1664-2392

VL - 13

SP - 1

EP - 14

JO - Frontiers in Endocrinology

JF - Frontiers in Endocrinology

M1 - 926210

ER -

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

Abstract

Bibliographical note

UN SDGs

Keywords

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