Promise and Challenge of β‑Lactone Electrophiles to Target Aspartate 12 of Mutant KRASG12D

The clinical success of covalent KRASG12C inhibition prompts further expansion of the concept to target non-cysteine oncogenic mutation sites as in KRASG12D. This endeavor was hampered by the lack of suitable electrophiles for the selective, covalent eng...

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Main Author:	Balázs Budai (21692320) (author)
Other Authors:	Andrea Vaupel (3038118) (author), Callum J. Dickson (2820142) (author), Kim S. Beyer (2819308) (author), Daniel A. Guthy (12488602) (author), Nils Ostermann (1780516) (author), Lynn M. McGregor (1273941) (author), Ruben De Kanter (21692323) (author), Andreas Weiss (135692) (author), Markus Linder (15999) (author), Emine Sager (10776431) (author), Claudio Bomio-Confaglia (14141197) (author), Rupert Proctor (21692326) (author), Catherine Leblanc (216034) (author), Jun Yuan (356273) (author), Simona Cotesta (2296576) (author), Rainer Wilcken (509958) (author), Aaron D. Danilack (11585923) (author), Francisco Garcia (6534794) (author), Phuong Rogemoser (18435753) (author), Malika Kazic-Legueux (14141209) (author), Ziyang Zhang (223533) (author), Qinheng Zheng (3328941) (author), Kevan M. Shokat (140265) (author), Saskia M. Brachmann (14141224) (author), Veronika Ehmke (1793932) (author)
Published:	2025
Subjects:	Biophysics Biochemistry Medicine Pharmacology Biotechnology Cancer Hematology Infectious Diseases Environmental Sciences not elsewhere classified Biological Sciences not elsewhere classified Mathematical Sciences not elsewhere classified Chemical Sciences not elsewhere classified ray crystallographic insights pd marker analysis balance specific reactivity g12d </ sup g12c </ sup bearing covalent inhibitors structure – activity quantum chemical calculations generated substituted β target aspartate 12 target non aspartate 12 covalent engagement wide profiling synthetic chemistry stability correlations recent discovery optimization strategy new opportunities metabolic stability medicinal chemistry inhibition prompts herein describe drug discovery covalent kras clinical success
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Promise and Challenge of β‑Lactone Electrophiles to Target Aspartate 12 of Mutant KRAS<sup>G12D</sup>

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