Selective and noncovalent targeting of RAS mutants for inhibition and degradation
Abstract
AbstractActivating mutants of RAS are commonly found in human cancers, but to date selective targeting of RAS in the clinic has been limited to KRAS(G12C) through covalent inhibitors. Here, we report a monobody, termed 12VC1, that recognizes the active state of both KRAS(G12V) and KRAS(G12C) up to 400-times more tightly than wild-type KRAS. The crystal structures reveal that 12VC1 recognizes the mutations through a shallow pocket, and 12VC1 competes against RAS-effector interaction. When expressed intracellularly, 12VC1 potently inhibits ERK activation and the proliferation of RAS-driven cancer cell lines in vitro and in mouse xenograft models. 12VC1 fused to VHL selectively degrades the KRAS mutants and provides more extended suppression of mutant RAS activity than inhibition by 12VC1 alone. These results demonstrate the feasibility of selective targeting and degradation of KRAS mutants in the active state with noncovalent reagents and provide a starting point for designing noncovalent therapeutics against oncogenic RAS mutants.
- Authors:
-
[3];
[2]
- New York Univ. (NYU), NY (United States). Perlmutter Cancer Center
- New York Univ. (NYU), NY (United States). Perlmutter Cancer Center and Grossman School of Medicine
- New York Univ. (NYU), NY (United States)
- Medical Univ. of South Carolina, Charleston, SC (United States); Ralph H. Johnson VA Medical Center, Charleston, SC (United States)
- Publication Date:
- Research Org.:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE Office of Science (SC); National Institutes of Health (NIH); Cancer Center Support Grant
- OSTI Identifier:
- 1806319
- Alternate Identifier(s):
- OSTI ID: 1818360
- Grant/Contract Number:
- AC02-06CH11357; R35 GM127040; R01 CA194864; R21 CA201717; R01 CA212608; P30CA016087
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Communications
- Additional Journal Information:
- Journal Volume: 12; Journal Issue: 1; Journal ID: ISSN 2041-1723
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 60 APPLIED LIFE SCIENCES; drug discovery; oncogenes
Citation Formats
Teng, Kai Wen, Tsai, Steven T., Hattori, Takamitsu, Fedele, Carmine, Koide, Akiko, Yang, Chao, Hou, Xuben, Zhang, Yingkai, Neel, Benjamin G., O’Bryan, John P., and Koide, Shohei. Selective and noncovalent targeting of RAS mutants for inhibition and degradation. United States: N. p., 2021.
Web. doi:10.1038/s41467-021-22969-5.
Teng, Kai Wen, Tsai, Steven T., Hattori, Takamitsu, Fedele, Carmine, Koide, Akiko, Yang, Chao, Hou, Xuben, Zhang, Yingkai, Neel, Benjamin G., O’Bryan, John P., & Koide, Shohei. Selective and noncovalent targeting of RAS mutants for inhibition and degradation. United States. https://doi.org/10.1038/s41467-021-22969-5
Teng, Kai Wen, Tsai, Steven T., Hattori, Takamitsu, Fedele, Carmine, Koide, Akiko, Yang, Chao, Hou, Xuben, Zhang, Yingkai, Neel, Benjamin G., O’Bryan, John P., and Koide, Shohei. Tue .
"Selective and noncovalent targeting of RAS mutants for inhibition and degradation". United States. https://doi.org/10.1038/s41467-021-22969-5. https://www.osti.gov/servlets/purl/1806319.
@article{osti_1806319,
title = {Selective and noncovalent targeting of RAS mutants for inhibition and degradation},
author = {Teng, Kai Wen and Tsai, Steven T. and Hattori, Takamitsu and Fedele, Carmine and Koide, Akiko and Yang, Chao and Hou, Xuben and Zhang, Yingkai and Neel, Benjamin G. and O’Bryan, John P. and Koide, Shohei},
abstractNote = {AbstractActivating mutants of RAS are commonly found in human cancers, but to date selective targeting of RAS in the clinic has been limited to KRAS(G12C) through covalent inhibitors. Here, we report a monobody, termed 12VC1, that recognizes the active state of both KRAS(G12V) and KRAS(G12C) up to 400-times more tightly than wild-type KRAS. The crystal structures reveal that 12VC1 recognizes the mutations through a shallow pocket, and 12VC1 competes against RAS-effector interaction. When expressed intracellularly, 12VC1 potently inhibits ERK activation and the proliferation of RAS-driven cancer cell lines in vitro and in mouse xenograft models. 12VC1 fused to VHL selectively degrades the KRAS mutants and provides more extended suppression of mutant RAS activity than inhibition by 12VC1 alone. These results demonstrate the feasibility of selective targeting and degradation of KRAS mutants in the active state with noncovalent reagents and provide a starting point for designing noncovalent therapeutics against oncogenic RAS mutants.},
doi = {10.1038/s41467-021-22969-5},
journal = {Nature Communications},
number = 1,
volume = 12,
place = {United States},
year = {Tue May 11 00:00:00 EDT 2021},
month = {Tue May 11 00:00:00 EDT 2021}
}
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