Article-summary-9-30-24
Article title
Targeting cancer with small-molecule pan-KRAS degraders
Journal
Science
Tags
PROTAC, Drug screening
Introduction
KRAS is a vital drug target owing to its frequent mutation in cancer cells. Hitherto, small molecule drugs targeting KRAS 1) suffer from their specificity, that is, uncapable of binding various KRAS mutation discovered in disease. 2) not well-developed in their PROTAC forms. Developing pan-KRAS PROTAC degraders help addressing problems above. Recently, pan-KRAS small molecule inhibitor was developed (2023, Nature). This work aims to apply this pan-KRAS inhibitors to PROTAC.
This work
Here, this work presented a PROTAC molecule (ACBI3) that can target 13 out of 17 disease-related KRAS mutants. Based on structure-guided rational design and sequential experiments in cells and in mouse. Extra in cell experiments validated that ACBI3 intervenes oncogenic (MAPK) pathways and cancer cell proliferation. Therefore, based on elaborate in cell and in mouse assays, this work confirmed that ACBI3 is a potential PROTAC solution to target pan-KRAS.
Details of drug screening and design is not discussed in article.