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Discovery of cell active macrocyclic peptides with on-target inhibition of KRAS signaling
Macrocyclic peptides have the potential to address intracellular protein–protein interactions (PPIs) of high value therapeutic targets that have proven largely intractable to small molecules. Here, we report broadly applicable lessons for applying this modality to intracellular targets and specifica...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society of Chemistry
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8672774/ https://www.ncbi.nlm.nih.gov/pubmed/35024121 http://dx.doi.org/10.1039/d1sc05187c |
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author | Lim, Shuhui Boyer, Nicolas Boo, Nicole Huang, Chunhui Venkatachalam, Gireedhar Angela Juang, Yu-Chi Garrigou, Michael Kaan, Hung Yi Kristal Duggal, Ruchia Peh, Khong Ming Sadruddin, Ahmad Gopal, Pooja Yuen, Tsz Ying Ng, Simon Kannan, Srinivasaraghavan Brown, Christopher J. Verma, Chandra S. Orth, Peter Peier, Andrea Ge, Lan Yu, Xiang Bhatt, Bhavana Chen, Feifei Wang, Erjia Li, Nianyu Jason Gonzales, Raymond J. Stoeck, Alexander Henry, Brian Sawyer, Tomi K. Lane, David P. Johannes, Charles W. Biswas, Kaustav Partridge, Anthony W. |
author_facet | Lim, Shuhui Boyer, Nicolas Boo, Nicole Huang, Chunhui Venkatachalam, Gireedhar Angela Juang, Yu-Chi Garrigou, Michael Kaan, Hung Yi Kristal Duggal, Ruchia Peh, Khong Ming Sadruddin, Ahmad Gopal, Pooja Yuen, Tsz Ying Ng, Simon Kannan, Srinivasaraghavan Brown, Christopher J. Verma, Chandra S. Orth, Peter Peier, Andrea Ge, Lan Yu, Xiang Bhatt, Bhavana Chen, Feifei Wang, Erjia Li, Nianyu Jason Gonzales, Raymond J. Stoeck, Alexander Henry, Brian Sawyer, Tomi K. Lane, David P. Johannes, Charles W. Biswas, Kaustav Partridge, Anthony W. |
author_sort | Lim, Shuhui |
collection | PubMed |
description | Macrocyclic peptides have the potential to address intracellular protein–protein interactions (PPIs) of high value therapeutic targets that have proven largely intractable to small molecules. Here, we report broadly applicable lessons for applying this modality to intracellular targets and specifically for advancing chemical matter to address KRAS, a protein that represents the most common oncogene in human lung, colorectal and pancreatic cancers yet is one of the most challenging targets in human disease. Specifically, we focused on KRpep-2d, an arginine-rich KRAS-binding peptide with a disulfide-mediated macrocyclic linkage and a protease-sensitive backbone. These latter redox and proteolytic labilities obviated cellular activity. Extensive structure–activity relationship studies involving macrocyclic linker replacement, stereochemical inversion, and backbone α-methylation, gave a peptide with on-target cellular activity. However, we uncovered an important generic insight – the arginine-dependent cell entry mechanism limited its therapeutic potential. In particular, we observed a strong correlation between net positive charge and histamine release in an ex vivo assay, thus making this series unsuitable for advancement due to the potentially fatal consequences of mast cell degranulation. This observation should signal to researchers that cationic-mediated cell entry – an approach that has yet to succeed in the clinic despite a long history of attempts – carries significant therapy-limiting safety liabilities. Nonetheless, the cell-active molecules identified here validate a unique inhibitory epitope on KRAS and thus provide valuable molecular templates for the development of therapeutics that are desperately needed to address KRAS-driven cancers – some of the most treatment-resistant human malignancies. |
format | Online Article Text |
id | pubmed-8672774 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | The Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-86727742022-01-11 Discovery of cell active macrocyclic peptides with on-target inhibition of KRAS signaling Lim, Shuhui Boyer, Nicolas Boo, Nicole Huang, Chunhui Venkatachalam, Gireedhar Angela Juang, Yu-Chi Garrigou, Michael Kaan, Hung Yi Kristal Duggal, Ruchia Peh, Khong Ming Sadruddin, Ahmad Gopal, Pooja Yuen, Tsz Ying Ng, Simon Kannan, Srinivasaraghavan Brown, Christopher J. Verma, Chandra S. Orth, Peter Peier, Andrea Ge, Lan Yu, Xiang Bhatt, Bhavana Chen, Feifei Wang, Erjia Li, Nianyu Jason Gonzales, Raymond J. Stoeck, Alexander Henry, Brian Sawyer, Tomi K. Lane, David P. Johannes, Charles W. Biswas, Kaustav Partridge, Anthony W. Chem Sci Chemistry Macrocyclic peptides have the potential to address intracellular protein–protein interactions (PPIs) of high value therapeutic targets that have proven largely intractable to small molecules. Here, we report broadly applicable lessons for applying this modality to intracellular targets and specifically for advancing chemical matter to address KRAS, a protein that represents the most common oncogene in human lung, colorectal and pancreatic cancers yet is one of the most challenging targets in human disease. Specifically, we focused on KRpep-2d, an arginine-rich KRAS-binding peptide with a disulfide-mediated macrocyclic linkage and a protease-sensitive backbone. These latter redox and proteolytic labilities obviated cellular activity. Extensive structure–activity relationship studies involving macrocyclic linker replacement, stereochemical inversion, and backbone α-methylation, gave a peptide with on-target cellular activity. However, we uncovered an important generic insight – the arginine-dependent cell entry mechanism limited its therapeutic potential. In particular, we observed a strong correlation between net positive charge and histamine release in an ex vivo assay, thus making this series unsuitable for advancement due to the potentially fatal consequences of mast cell degranulation. This observation should signal to researchers that cationic-mediated cell entry – an approach that has yet to succeed in the clinic despite a long history of attempts – carries significant therapy-limiting safety liabilities. Nonetheless, the cell-active molecules identified here validate a unique inhibitory epitope on KRAS and thus provide valuable molecular templates for the development of therapeutics that are desperately needed to address KRAS-driven cancers – some of the most treatment-resistant human malignancies. The Royal Society of Chemistry 2021-11-25 /pmc/articles/PMC8672774/ /pubmed/35024121 http://dx.doi.org/10.1039/d1sc05187c Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by/3.0/ |
spellingShingle | Chemistry Lim, Shuhui Boyer, Nicolas Boo, Nicole Huang, Chunhui Venkatachalam, Gireedhar Angela Juang, Yu-Chi Garrigou, Michael Kaan, Hung Yi Kristal Duggal, Ruchia Peh, Khong Ming Sadruddin, Ahmad Gopal, Pooja Yuen, Tsz Ying Ng, Simon Kannan, Srinivasaraghavan Brown, Christopher J. Verma, Chandra S. Orth, Peter Peier, Andrea Ge, Lan Yu, Xiang Bhatt, Bhavana Chen, Feifei Wang, Erjia Li, Nianyu Jason Gonzales, Raymond J. Stoeck, Alexander Henry, Brian Sawyer, Tomi K. Lane, David P. Johannes, Charles W. Biswas, Kaustav Partridge, Anthony W. Discovery of cell active macrocyclic peptides with on-target inhibition of KRAS signaling |
title | Discovery of cell active macrocyclic peptides with on-target inhibition of KRAS signaling |
title_full | Discovery of cell active macrocyclic peptides with on-target inhibition of KRAS signaling |
title_fullStr | Discovery of cell active macrocyclic peptides with on-target inhibition of KRAS signaling |
title_full_unstemmed | Discovery of cell active macrocyclic peptides with on-target inhibition of KRAS signaling |
title_short | Discovery of cell active macrocyclic peptides with on-target inhibition of KRAS signaling |
title_sort | discovery of cell active macrocyclic peptides with on-target inhibition of kras signaling |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8672774/ https://www.ncbi.nlm.nih.gov/pubmed/35024121 http://dx.doi.org/10.1039/d1sc05187c |
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