Reengineering of a Proteomimetic Pan‐Ras Inhibitor into a Ras Degrader

Abstract Bifunctional ligands that can coax protein–protein interactions have become attractive therapeutic modalities. Herein, we describe conformationally defined helix dimers as proteomimetic molecular glues . The helix dimers can be rationally designed to engage helical protein interfaces. We previously described a synthetic Sos protein mimic, CHD SOS , as a Ras ligand that inhibits wild‐type and oncogenic Ras signaling. This Sos proteomimetic consisted of a crosslinked helix dimer (CHD) that reproduced two helical domains, termed αH and αI, from Sos. The native αH helix of Sos constitutes the primary contact surface for Sos, while αI has minimal engagement. We conjectured that the αI domain of CHD SOS could be reengineered to preserve Ras binding, while engaging another protein to fully leverage the contact residues available in a proteomimetic. Herein, we incorporate a second distinct binding epitope into CHD SOS , thereby generating a bispecific proteomimetic. This secondary epitope was designed based on the p53 activation domain to engage the E3 ligase MDM2 and induce complexation with Ras. The resulting lead proteomimetic, CHD BI4 , associates with both MDM2 and Ras and demonstrates reduction of cellular Ras levels. Overall, the study offers a proof of concept for the development of a bispecific proteomimetic scaffold to target multiple protein interfaces.