Normal and oncogenic RAS signalling pathway along with inhibitors.
KRAS G12 mutations drive aggressive cancers. Once considered undruggable, several strategies evolved in the last decade to target OFF and ON states. Approval of inhibitors and the growing pipeline offer great hope to patients.
This study focuses on the exploration of a novel synthetic route for the KRASG12C inhibitor. The approach avoids the formation of regioselective by-products and eliminates the need for high temperatures and nitric acid.
We show that a bottlebrush polymer-antisense oligonucleotide conjugate (termed pacDNA) enters cancer cells by scavenger receptor-mediated endocytosis and micropinocytosis, trafficks via the endolysosomal pathway, and functions as a steric blocker.
Bis-thiazole peptidomimetic TTh2 selectively binds and stabilizes the KRAS promoter G-quadruplex, leading to KRAS downregulation and inhibition of MAPK and Akt/mTOR pathways, demonstrating a novel strategy for targeting ''undruggable'' oncogenes.