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Title: KRAS G12C Drug Development: Discrimination between Switch II Pocket Configurations Using Hydrogen/Deuterium-Exchange Mass Spectrometry

Abstract

KRAS G12C, the most common RAS mutation found in non-small-cell lung cancer, has been the subject of multiple recent covalent small-molecule inhibitor campaigns including efforts directed at the guanine nucleotide pocket and separate work focused on an inducible pocket adjacent to the switch motifs. Multiple conformations of switch II have been observed, suggesting that switch II pocket (SIIP) binders may be capable of engaging a range of KRAS conformations. Here we report the use of hydrogen/deuterium-exchange mass spectrometry (HDX MS) to discriminate between conformations of switch II induced by two chemical classes of SIIP binders. We investigated the structural basis for differences in HDX MS using X-ray crystallography and discovered a new SIIP configuration in response to binding of a quinazoline chemotype. These results have implications for structure-guided drug design targeting the RAS SIIP.

Authors:
; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOD
OSTI Identifier:
1408110
Resource Type:
Journal Article
Resource Relation:
Journal Name: Structure; Journal Volume: 25; Journal Issue: 9
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Lu, Jia, Harrison, Rane A., Li, Lianbo, Zeng, Mei, Gondi, Sudershan, Scott, David, Gray, Nathanael S., Engen, John R., and Westover, Kenneth D. KRAS G12C Drug Development: Discrimination between Switch II Pocket Configurations Using Hydrogen/Deuterium-Exchange Mass Spectrometry. United States: N. p., 2017. Web. doi:10.1016/j.str.2017.07.003.
Lu, Jia, Harrison, Rane A., Li, Lianbo, Zeng, Mei, Gondi, Sudershan, Scott, David, Gray, Nathanael S., Engen, John R., & Westover, Kenneth D. KRAS G12C Drug Development: Discrimination between Switch II Pocket Configurations Using Hydrogen/Deuterium-Exchange Mass Spectrometry. United States. doi:10.1016/j.str.2017.07.003.
Lu, Jia, Harrison, Rane A., Li, Lianbo, Zeng, Mei, Gondi, Sudershan, Scott, David, Gray, Nathanael S., Engen, John R., and Westover, Kenneth D. 2017. "KRAS G12C Drug Development: Discrimination between Switch II Pocket Configurations Using Hydrogen/Deuterium-Exchange Mass Spectrometry". United States. doi:10.1016/j.str.2017.07.003.
@article{osti_1408110,
title = {KRAS G12C Drug Development: Discrimination between Switch II Pocket Configurations Using Hydrogen/Deuterium-Exchange Mass Spectrometry},
author = {Lu, Jia and Harrison, Rane A. and Li, Lianbo and Zeng, Mei and Gondi, Sudershan and Scott, David and Gray, Nathanael S. and Engen, John R. and Westover, Kenneth D.},
abstractNote = {KRAS G12C, the most common RAS mutation found in non-small-cell lung cancer, has been the subject of multiple recent covalent small-molecule inhibitor campaigns including efforts directed at the guanine nucleotide pocket and separate work focused on an inducible pocket adjacent to the switch motifs. Multiple conformations of switch II have been observed, suggesting that switch II pocket (SIIP) binders may be capable of engaging a range of KRAS conformations. Here we report the use of hydrogen/deuterium-exchange mass spectrometry (HDX MS) to discriminate between conformations of switch II induced by two chemical classes of SIIP binders. We investigated the structural basis for differences in HDX MS using X-ray crystallography and discovered a new SIIP configuration in response to binding of a quinazoline chemotype. These results have implications for structure-guided drug design targeting the RAS SIIP.},
doi = {10.1016/j.str.2017.07.003},
journal = {Structure},
number = 9,
volume = 25,
place = {United States},
year = 2017,
month = 9
}
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