posted on 2023-12-06, 13:06authored byChristian Nilewski, Sharada Labadie, Binqing Wei, Sushant Malhotra, Steven Do, Lewis Gazzard, Li Liu, Cheng Shao, Jeremy Murray, Yevgeniy Izrayelit, Amy Gustafson, Nicholas F. Endres, Fang Ma, Xin Ye, Jun Zou, Marie Evangelista
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.