The missing link between (un)druggable and degradable KRAS

A commentary on the first PROTAC that degrades KRas-G12C in cells

Professor Tate, Dr Elena De Vita, and Dr María Maneiro Rey were invited to introduce, to the broad audience of ACS Central Science, the recent findings on the first in cellulo active KRas^G12C PROTAC developed by Crews laboratory (published in the same issue of ACS Central Science).

In this first reaction piece, the authors had the opportunity to take a step back and reflect on the status of both the PROTAC and the Ras GTPase targeting fields. Despite the undeniable substantial advancement in both areas, clear challenges are still foreseeable for researchers in the near future.

Questions surrounding the possibility of developing a non-covalent KRas PROTAC to target multiple malignant forms in cancer remain unanswered. In addition, the development of novel tools allowing for the straightforward design of effective PROTACs, thus reducing the current time required for optimization, are still required.