Synfacts 2020; 16(08): 0971
DOI: 10.1055/s-0040-1706815
Chemistry in Medicine and Biology
© Georg Thieme Verlag Stuttgart · New York

Covalent Inhibition of Ras G12C with a Stapled Peptidomimetic

Dirk Trauner
Bryan S. Matsuura
Yoo DY, Hauser AD, Joy ST, Bar-Sagi D. * Arora PS. * New York University and New York University School of Medicine, USA
Covalent Targeting of Ras G12C by Rationally Designed Peptidomimetics.

ACS Chem. Biol. 2020;
15: 1604-1612
Further Information

Publication History

Publication Date:
21 July 2020 (online)



Ras proteins are central to several pathways involved in cell proliferation and survival. Dysregulation in Ras signaling is implicated in nearly 30% of all human tumors, and therefore represents an important target in oncology. Bar-Sagi, Arora, and co-workers describe the development of a covalent inhibitor of mutant Ras G12C, using a stapled peptidomimetic scaffold based on the nucleotide exchange factor Son of Sevenless (SoS).



Inhibitor A was synthesized using SPPS and includes an interesting hydrogen-bond surrogate (HBS) motif that is generated from an on-resin ring-closing metathesis of an internal N-allyl glycine to an N-terminal hexenoic amide. Binding of A to Ras G12C triggers proximity-induced cysteine alkylation of A’s sulfonamide motif. Biochemical assays indicate that the G12C mutation is necessary for Ras inhibition and modulation of downstream effects by A.