Nature Structural and Molecular Biology, volume 25, issue 6, pages 454-462
The reactivity-driven biochemical mechanism of covalent KRASG12C inhibitors
Rasmus Hansen
1
,
Ulf Peters
1
,
Anjali Babbar
1
,
Yuching Chen
1
,
Jun Feng
1
,
Matthew R. Janes
1
,
Lian-Sheng Li
1
,
Pingda Ren
1, 2
,
Yi Liu
1, 2
,
Patrick P Zarrinkar
1
1
Wellspring Biosciences, Inc., San Diego, USA
|
2
Kura Oncology, Inc., San Diego, USA
|
Publication type: Journal Article
Publication date: 2018-05-14
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 16.8
ISSN: 15459993, 15459985
Molecular Biology
Structural Biology
Abstract
Activating mutations in KRAS are among the most common tumor driver mutations. Until recently, KRAS had been considered undruggable with small molecules; the discovery of the covalent KRASG12C inhibitors ARS-853 and ARS-1620 has demonstrated that it is feasible to inhibit KRAS with high potency in cells and animals. Although the biological activity of these inhibitors has been described, the biochemical mechanism of how the compounds achieve potent inhibition remained incompletely understood. We now show that the activity of ARS-853 and ARS-1620 is primarily driven by KRAS-mediated catalysis of the chemical reaction with Cys12 in human KRASG12C, while the reversible binding affinity is weak, in the hundreds of micromolar or higher range. The mechanism resolves how an induced, shallow and dynamic pocket not expected to support high-affinity binding of small molecules can nevertheless be targeted with potent inhibitors and may be applicable to other targets conventionally considered undruggable. Kinetic and structural analyses show that the activity of two covalent inhibitors of human KRASG12C, which initially bind to a shallow pocket with low affinity, is driven by KRAS-mediated catalysis of the chemical reaction with Cys12.
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Hansen R. et al. The reactivity-driven biochemical mechanism of covalent KRASG12C inhibitors // Nature Structural and Molecular Biology. 2018. Vol. 25. No. 6. pp. 454-462.
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Hansen R., Peters U., Babbar A., Chen Y., Feng J., Janes M. R., Li L., Ren P., Liu Y., Zarrinkar P. P. The reactivity-driven biochemical mechanism of covalent KRASG12C inhibitors // Nature Structural and Molecular Biology. 2018. Vol. 25. No. 6. pp. 454-462.
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TY - JOUR
DO - 10.1038/s41594-018-0061-5
UR - https://doi.org/10.1038/s41594-018-0061-5
TI - The reactivity-driven biochemical mechanism of covalent KRASG12C inhibitors
T2 - Nature Structural and Molecular Biology
AU - Hansen, Rasmus
AU - Peters, Ulf
AU - Babbar, Anjali
AU - Chen, Yuching
AU - Feng, Jun
AU - Janes, Matthew R.
AU - Li, Lian-Sheng
AU - Ren, Pingda
AU - Liu, Yi
AU - Zarrinkar, Patrick P
PY - 2018
DA - 2018/05/14 00:00:00
PB - Springer Nature
SP - 454-462
IS - 6
VL - 25
SN - 1545-9993
SN - 1545-9985
ER -
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@article{2018_Hansen,
author = {Rasmus Hansen and Ulf Peters and Anjali Babbar and Yuching Chen and Jun Feng and Matthew R. Janes and Lian-Sheng Li and Pingda Ren and Yi Liu and Patrick P Zarrinkar},
title = {The reactivity-driven biochemical mechanism of covalent KRASG12C inhibitors},
journal = {Nature Structural and Molecular Biology},
year = {2018},
volume = {25},
publisher = {Springer Nature},
month = {may},
url = {https://doi.org/10.1038/s41594-018-0061-5},
number = {6},
pages = {454--462},
doi = {10.1038/s41594-018-0061-5}
}
Cite this
MLA
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Hansen, Rasmus, et al. “The reactivity-driven biochemical mechanism of covalent KRASG12C inhibitors.” Nature Structural and Molecular Biology, vol. 25, no. 6, May. 2018, pp. 454-462. https://doi.org/10.1038/s41594-018-0061-5.