https://video.igem.org/videos/watch/38b2a0b2-fe4f-4143-a99e-2aae52f5f4a3 Title: AETh3R Description: AETh3R is a dual therapeutic approach for KRAS-mutant, wild-type p53 NSCLC built on peptide-PROTAC (p-PROTAC) technology. It targets mutant KRAS, whose persistent activation sustains proliferative signalling, and MDM2, which suppresses p53. By redirecting both toward the cell's own degradation machinery we aim to shut down oncogenic KRAS signalling and restore p53-mediated tumour suppression at the same time, removing the proteins rather than occupying them, so the cell's natural apoptotic and cell-cycle controls can resume. This is achieved through two heterobifunctional p-PROTACs, each built from a target-binding peptide, a linker, and a ligand recruiting the VHL E3 ubiquitin ligase: one against mutant KRAS, one against MDM2. Engaging target and VHL simultaneously brings the two into proximity, driving ubiquitination and proteasomal degradation. To address the central limitation of peptide therapeutics - intracellular delivery - the design incorporates lipid nanoparticles. Through computational modelling and experimental validation we aim for a system that reaches intracellular KRAS and MDM2 while preferentially recognising oncogenic KRAS over wild-type, and selectively targeting tumour cells where MDM2 is overexpressed. Wiki | Official Page Thu, 29 Oct 2026 21:22:07 GMT https://validator.w3.org/feed/docs/rss2.html PeerTube - https://video.igem.org https://video.igem.org/client/assets/images/icons/icon-1500x1500.png https://video.igem.org/videos/watch/38b2a0b2-fe4f-4143-a99e-2aae52f5f4a3 All rights reserved, unless otherwise specified in the terms specified at https://video.igem.org/about and potential licenses granted by each content's rightholder.