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Structure-Based Design and Evaluation of Reversible KRAS G13D Inhibitors
Christian Nilewski1, Sharada Labadie1, Binqing Wei1
1Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States.
Abstract:
Oncogenic KRAS mutations were identified decades ago, yet the selective inhibition of specific KRAS mutant proteins represents an ongoing challenge. Recent progress has been made in targeting certain P-loop mutant proteins, in particular KRAS G12C, for which the covalent inhibition of the GDP state via the Switch II pocket is now a clinically validated strategy. Inhibition of other KRAS mutant proteins such as KRAS G13D, on the other hand, still requires clinical validation. The remoteness of the D13 residue relative to the Switch II pocket in combination with the solvent exposure and conformational flexibility of the D13 side chain, as well as the difficulties of targeting carboxylate residues covalently, renders this specific protein particularly challenging to target selectively. In this report, we describe the design and evaluation of potent and KRAS G13D-selective reversible inhibitors. Subnanomolar binding to the GDP state Switch II pocket and biochemical selectivity over WT KRAS are achieved by leveraging a salt bridge with D13.
Insights
Researchers developed new reversible inhibitors targeting KRAS G13D mutations, a challenging cancer target. These inhibitors achieve high potency and selectivity by forming a salt bridge with the D13 residue.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Oncogenic KRAS mutations are well-established drivers of various cancers.
- Targeting KRAS G12C has shown clinical success through covalent inhibition.
- Selective inhibition of other KRAS mutants, like KRAS G13D, remains a significant challenge.
Purpose of the Study:
- To design and evaluate novel, potent, and selective inhibitors for KRAS G13D.
- To overcome the challenges associated with targeting the KRAS G13D mutation.
Main Methods:
- Structure-based drug design leveraging interactions with the D13 residue.
- Evaluation of inhibitor binding affinity to the GDP-bound state of KRAS G13D.
- Biochemical assays to assess selectivity against wild-type (WT) KRAS.
Main Results:
- Development of potent reversible inhibitors with subnanomolar binding affinity.
- Achieved high biochemical selectivity for KRAS G13D over WT KRAS.
- Inhibitor design utilizes a salt bridge interaction with the D13 residue.
Conclusions:
- Successful design of KRAS G13D-selective reversible inhibitors.
- The developed inhibitors represent a promising strategy for targeting KRAS G13D-mutant cancers.
- Leveraging specific residue interactions, like the D13 salt bridge, is effective for selective KRAS inhibition.
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