Abstract

KRAS is a major oncogenic driver, but therapeutic targeting remains limited by restricted druggability, pathway reactivation, and resistance to allele-specific inhibitors. Targeted protein degradation (TPD) offers a complementary approach enabling catalytic, sustained suppression of KRAS signaling. We developed panKRAS degraders using a structure-guided strategy combining reversible KRAS binders with VHL-recruiting PROTACs. High-affinity binders derived from a fragment-first approach were translated into degraders through optimization of linker design and ternary complex formation. The degrader ACBI3 showed broad activity but limited efficacy against GTP-loaded (KRAS ON) mutants due to insufficient ternary complex stability. Biophysical and cooperativity-driven optimization led to ACBI4, a next-generation degrader forming highly stable ternary complexes independent of nucleotide state. ACBI4 enables potent pan-allelic degradation, including ON-biased mutants, establishing KRAS degradation as a viable therapeutic modality and positioning ACBI4 as a pioneering panKRAS ON/OFF chemical probe.

Citation Format:

Andreas Antonius. Mantoulidis. Title of the talk: KRAS - Degrading the Undruggable [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr IA06.