Targeting oncogenic KRasG13C with nucleotide-based covalent inhibitors

Area of Science:

• Oncology
• Molecular Biology
• Medicinal Chemistry

Background:

• Ras proteins, including KRas, are frequently mutated in human cancers, driving tumor growth.
• The KRasG13C mutation is a significant oncogenic driver that has historically been challenging to target therapeutically.

Purpose of the Study:

• To design, synthesize, and evaluate novel nucleotide-based covalent inhibitors specifically for KRasG13C.
• To investigate the molecular properties and anti-cancer potential of these inhibitors.

Main Methods:

• Structure-based drug design and chemical synthesis of covalent inhibitors.
• Biochemical assays, kinetic studies, and mass spectrometry to assess inhibitor properties.
• X-ray crystallography to determine the binding mode of inhibitors with KRasG13C.
• Cellular assays to evaluate the impact on oncogenic signaling.

Main Results:

• Successful design and synthesis of nucleotide-based covalent inhibitors for KRasG13C.
• Demonstration of promising molecular properties and covalent modification of KRasG13C.
• X-ray structures reveal the first covalent complexes of KRasG13C with GDP analogs.
• Inhibitors prevent SOS-catalyzed nucleotide exchange and block oncogenic signaling in cells.

Conclusions:

• Nucleotide-based covalent inhibitors represent a promising therapeutic strategy for KRasG13C-driven cancers.
• Covalent modification of KRasG13C effectively inhibits its oncogenic function.
• This work provides a foundation for developing new targeted cancer therapies.