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Published on: January 16, 2020
Promise and Challenge of β-Lactone Electrophiles to Target Aspartate 12 of Mutant KRASG12D
Balázs Budai1, Andrea Vaupel1, Callum J Dickson2
1Novartis BioMedical Research, 4056 Basel, Switzerland.
Abstract:
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 engagement of aspartate. Thanks to the recent discovery of β-lactone-bearing covalent inhibitors, new opportunities are emerging. Based on X-ray crystallographic insights and quantum chemical calculations, we herein describe the elucidation of structure-activity and -stability correlations to advance such electrophiles for drug discovery. Guided by predictions of transition state barrier heights for the attack of aspartate 12 at the β-lactone electrophile and structure-based design, we generated substituted β-lactones aiming to balance specific reactivity and chemical and metabolic stability. Our optimization strategy is driven by MS-based and cellular covalent target occupancy assays and PD marker analysis, proteome-wide profiling, and synthetic chemistry. With this work, we aim to expand the use of β-lactones as chemoselective electrophiles in medicinal chemistry.
Insights
Researchers developed novel beta-lactone covalent inhibitors to target KRAS G12D mutations, overcoming challenges in selectively engaging aspartate for potential cancer therapies.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Oncology
Background:
- Covalent KRAS G12C inhibitors show clinical success, driving interest in targeting other KRAS mutations like KRAS G12D.
- Targeting KRAS G12D is challenging due to the lack of suitable electrophiles for covalent aspartate engagement.
Purpose of the Study:
- To develop novel beta-lactone electrophiles for selective covalent inhibition of KRAS G12D.
- To elucidate structure-activity and -stability relationships for optimizing beta-lactone inhibitors.
Main Methods:
- X-ray crystallography and quantum chemical calculations to understand interactions.
- Structure-based design and synthetic chemistry to generate substituted beta-lactones.
- MS-based assays, cellular target occupancy, and proteome-wide profiling for optimization.
Main Results:
- Generated substituted beta-lactones balancing reactivity, chemical, and metabolic stability.
- Demonstrated optimization driven by various assays and profiling techniques.
- Advanced the understanding of beta-lactones as chemoselective electrophiles.
Conclusions:
- Beta-lactones represent a promising class of electrophiles for covalent inhibition of KRAS G12D.
- This work expands the utility of beta-lactones in medicinal chemistry for targeted cancer therapies.
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