Pan RAS-binding compounds selected from a chemical library by inhibiting interaction between RAS and a reduced affinity intracellular antibody

Abstract Intracellular antibodies are valuable tools for target validation studies for clinical situations such as cancer. Recently we have shown that antibodies can be used for drug discovery in screening for chemical compounds surrogates by showing that compounds could be developed to the so-calle...

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Autores principales: Tomoyuki Tanaka, Jemima Thomas, Rob Van Montfort, Ami Miller, Terry Rabbitts
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Lenguaje:EN
Publicado: Nature Portfolio 2021
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Acceso en línea:https://doaj.org/article/c468ab122a7546998735702fb5e4d92b
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spelling oai:doaj.org-article:c468ab122a7546998735702fb5e4d92b2021-12-02T10:49:15ZPan RAS-binding compounds selected from a chemical library by inhibiting interaction between RAS and a reduced affinity intracellular antibody10.1038/s41598-021-81262-z2045-2322https://doaj.org/article/c468ab122a7546998735702fb5e4d92b2021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-81262-zhttps://doaj.org/toc/2045-2322Abstract Intracellular antibodies are valuable tools for target validation studies for clinical situations such as cancer. Recently we have shown that antibodies can be used for drug discovery in screening for chemical compounds surrogates by showing that compounds could be developed to the so-called undruggable RAS protein family. This method, called Antibody-derived compound (Abd) technology, employed intracellular antibodies binding to RAS in a competitive surface plasmon resonance chemical library screen. Success with this method requires a high affinity interaction between the antibody and the target. We now show that reduction in the affinity (dematuration) of the anti-active RAS antibody facilitates the screening of a chemical library using an in vitro AlphaScreen method. This identified active RAS specific-binding Abd compounds that inhibit the RAS-antibody interaction. One compound is shown to be a pan-RAS binder to KRAS, HRAS and NRAS-GTP proteins with a Kd of average 37 mM, offering the possibility of a new chemical series that interacts with RAS in the switch region where the intracellular antibody binds. This simple approach shows the druggability of RAS and is generally applicable to antibody-derived chemical library screening by affording flexibility through simple antibody affinity variation. This approach can be applied to find Abd compounds as surrogates of antibody-combining sites for novel drug development in a range of human diseases.Tomoyuki TanakaJemima ThomasRob Van MontfortAmi MillerTerry RabbittsNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Tomoyuki Tanaka
Jemima Thomas
Rob Van Montfort
Ami Miller
Terry Rabbitts
Pan RAS-binding compounds selected from a chemical library by inhibiting interaction between RAS and a reduced affinity intracellular antibody
description Abstract Intracellular antibodies are valuable tools for target validation studies for clinical situations such as cancer. Recently we have shown that antibodies can be used for drug discovery in screening for chemical compounds surrogates by showing that compounds could be developed to the so-called undruggable RAS protein family. This method, called Antibody-derived compound (Abd) technology, employed intracellular antibodies binding to RAS in a competitive surface plasmon resonance chemical library screen. Success with this method requires a high affinity interaction between the antibody and the target. We now show that reduction in the affinity (dematuration) of the anti-active RAS antibody facilitates the screening of a chemical library using an in vitro AlphaScreen method. This identified active RAS specific-binding Abd compounds that inhibit the RAS-antibody interaction. One compound is shown to be a pan-RAS binder to KRAS, HRAS and NRAS-GTP proteins with a Kd of average 37 mM, offering the possibility of a new chemical series that interacts with RAS in the switch region where the intracellular antibody binds. This simple approach shows the druggability of RAS and is generally applicable to antibody-derived chemical library screening by affording flexibility through simple antibody affinity variation. This approach can be applied to find Abd compounds as surrogates of antibody-combining sites for novel drug development in a range of human diseases.
format article
author Tomoyuki Tanaka
Jemima Thomas
Rob Van Montfort
Ami Miller
Terry Rabbitts
author_facet Tomoyuki Tanaka
Jemima Thomas
Rob Van Montfort
Ami Miller
Terry Rabbitts
author_sort Tomoyuki Tanaka
title Pan RAS-binding compounds selected from a chemical library by inhibiting interaction between RAS and a reduced affinity intracellular antibody
title_short Pan RAS-binding compounds selected from a chemical library by inhibiting interaction between RAS and a reduced affinity intracellular antibody
title_full Pan RAS-binding compounds selected from a chemical library by inhibiting interaction between RAS and a reduced affinity intracellular antibody
title_fullStr Pan RAS-binding compounds selected from a chemical library by inhibiting interaction between RAS and a reduced affinity intracellular antibody
title_full_unstemmed Pan RAS-binding compounds selected from a chemical library by inhibiting interaction between RAS and a reduced affinity intracellular antibody
title_sort pan ras-binding compounds selected from a chemical library by inhibiting interaction between ras and a reduced affinity intracellular antibody
publisher Nature Portfolio
publishDate 2021
url https://doaj.org/article/c468ab122a7546998735702fb5e4d92b
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