Pan-KRAS destruction with a single PROTAC

Most small-molecule drugs that target oncogenic Kirsten rat sarcoma virus (KRAS) mutants rely on interactions with variant-specific amino acid residues. However, a wide range of KRAS mutations are prevalent in human cancers, and undruggable variants pose a great challenge to the clinical treatment of KRAS-mutant tumors. In a paper published in Science, Popow et al. address this issue by designing a proteolysis-targeting chimera (PROTAC) that degrades a broad spectrum of KRAS variants.

A structure-based design approach yielded a potent KRAS-selective degrader that targets the switch II pocket, which is conserved across KRAS variants. The researchers coupled a previously used ligand to a linker together with a binding motif for the Von Hippel–Lindau (VHL) E3 ligase. Lead compound optimization improved stability and engagement with intracellular VHL, resulting in a PROTAC that efficiently degraded 13 out of 17 KRAS mutant variants in vitro. Unbiased mass spectrometry proteomics showed >50% protein depletion and detected only KRAS, indicating that the PROTAC is highly selective for KRAS. Pan-KRAS degradation suppressed oncogenic MAPK signaling and inhibited proliferation in cancer cell lines driven by diverse KRAS mutants. KRAS degradation was more than 10-fold more potent than KRAS inhibition. An in vivo optimized compound, called ACB13, caused regression of KRAS mutant tumors in mice.