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Strain-release alkylation of Asp12 enables mutant selective targeting of K-Ras-G12D
Qinheng Zheng1, Ziyang Zhang2,3, Keelan Z Guiley1
1Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, CA, USA.
Abstract:
K-Ras is the most commonly mutated oncogene in human cancer. The recently approved non-small cell lung cancer drugs sotorasib and adagrasib covalently capture an acquired cysteine in K-Ras-G12C mutation and lock it in a signaling-incompetent state. However, covalent inhibition of G12D, the most frequent K-Ras mutation particularly prevalent in pancreatic ductal adenocarcinoma, has remained elusive due to the lack of aspartate-targeting chemistry. Here we present a set of malolactone-based electrophiles that exploit ring strain to crosslink K-Ras-G12D at the mutant aspartate to form stable covalent complexes. Structural insights from X-ray crystallography and exploitation of the stereoelectronic requirements for attack of the electrophile allowed development of a substituted malolactone that resisted attack by aqueous buffer but rapidly crosslinked with the aspartate-12 of K-Ras in both GDP and GTP state. The GTP-state targeting allowed effective suppression of downstream signaling, and selective inhibition of K-Ras-G12D-driven cancer cell proliferation in vitro and xenograft growth in mice.
Insights
Researchers developed novel malolactone compounds to target the K-Ras-G12D mutation, a common driver in pancreatic cancer. These compounds form stable covalent bonds, inhibiting cancer cell growth and tumor progression.
Area of Science:
- Oncology
- Molecular Biology
- Medicinal Chemistry
Background:
- K-Ras mutations are key drivers in numerous human cancers.
- Current therapies target K-Ras-G12C but lack options for K-Ras-G12D, prevalent in pancreatic cancer.
- Targeting K-Ras-G12D is challenging due to the absence of suitable aspartate-targeting chemistry.
Purpose of the Study:
- To develop novel covalent inhibitors targeting the K-Ras-G12D mutation.
- To overcome the limitations of existing therapies by addressing the aspartate residue.
- To explore the potential of malolactone-based electrophiles for K-Ras inhibition.
Main Methods:
- Design and synthesis of malolactone-based electrophiles.
- Utilizing X-ray crystallography for structural insights.
- Assessing covalent crosslinking efficiency with K-Ras-G12D in GDP and GTP states.
- Evaluating inhibition of cancer cell proliferation and xenograft tumor growth in vitro and in vivo.
Main Results:
- Developed substituted malolactones that selectively crosslink K-Ras-G12D at Aspartate-12.
- Achieved stable covalent complex formation, resistant to buffer hydrolysis.
- Demonstrated effective suppression of downstream signaling in the GTP-bound state.
- Showed selective inhibition of K-Ras-G12D-driven cancer cell proliferation and xenograft growth.
Conclusions:
- Malolactone-based electrophiles represent a promising strategy for targeting K-Ras-G12D.
- This approach offers a potential therapeutic avenue for cancers driven by the K-Ras-G12D mutation.
- The developed compounds demonstrate efficacy in preclinical models, warranting further investigation.
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