Budai, Balazs, Vaupel, Andrea, Dickson, Callum, Beyer, Kim, Guthy, Daniel Alexander, Ostermann, Nils, McGregor, Lynn, de Kanter, Ruben, Weiss, Andreas-2, Linder, Markus-1, Sager, Emine, Bomio-Confaglia, Claudio, Leblanc, Catherine, Cotesta, Simona, Danilack, Aaron, Garcia, Francisco-1, Rogemoser, Phuong, Kazic-Legueux, Malika-1, Brachmann, Saskia, Ehmke, Veronika, Wilcken, Rainer, Proctor, Rupert, Yuan, Jun, Ziyang, Zhang, Zheng, Qinheng and Shokat, Kevan (2025) Promise and challenge of β-lactone electrophiles to target Asp12 of mutant KRASG12D. Journal of medicinal chemistry. ISSN 1520-4804; 0022-2623

Abstract

After decades of drug discovery research on KRAS inhibitors with the potential to achieve a transformative cancer treatment for some of the most prevalent cancer types, there is still an unmet need to identify KRASG12D mutant selective inhibitors. The early clinical success of a covalent targeting strategy for 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 selective, covalent engagement of aspartate. Thanks to the recent discovery of b-lactone-bearing covalent inhibitors of KRASG12D new opportunities for drug discovery are emerging. Based on structural insights from X-ray crystallography and quantum mechanical considerations, we herein describe our work on elucidation of structure-activity and structure-stability correlations to further advance such electrophiles for drug discovery. Guided by predictions of transition state barrier heights for attack of aspartate 12 at the β-lactone electrophile as well as by structure-based design, we generated substituted b-lactones with the aim to achieve a balance of specific reactivity, chemical and metabolic stability. Our optimization strategy was driven by MS-based and cellular covalent target occupancy assays and PD marker analysis, as well as proteome-wide profiling and synthetic chemistry. With an improved understanding of structure and reactivity in biological systems, we wish to expand the use of β-lactones as chemoselective electrophiles and catalyze further applications of covalent carboxylate targeting in medicinal chemistry and drug discovery.

Item Type:	Article
Date Deposited:	09 Aug 2025 00:45
Last Modified:	09 Aug 2025 00:45
URI:	https://oak.novartis.com/id/eprint/56771