Targeted protein degradation (TPD) using proteolysis targeting chimeras (PROTACs) has arisen as a powerful therapeutic modality for eliminating disease-causing proteins from cells. PROTACs employ heterobifunctional small molecules to chemically induce the proximity of target proteins with E3 ubiquitin ligases to ubiquitinate and degrade specific proteins via the proteasome. This study is to design and synthesize a series of novel PROTAC compounds targeting the KRAS G12C mutationwhich make up over 50% of all KRAS mutant LUAD (Lung Adenocarcinoma).
In our study, targets mutant KRAS G12C has been designed and developed which is composed of reversible non-covalent KRAS binder linked to E3. We conducted the design, synthesis, and evaluation of PROTAC KRAS degraders using the VHL or cereblon ligands, and different classes of non-covalent KRAS binder. I We fully determined the optimal linker lengths and types needed in our PROTAC molecules for potent and effective KRAS degradation.
Through extensive optimization of the linker and modifications of the KRAS binder portion of the compounds, we have discovered a set of exceptionally potent KRAS degraders with moderate membrane permeability and good plasma stability. More than 50 compounds were designed and synthesized using various linkers, E3 ligands and KRASG12C binders. Almost all compounds maintained good selectivity to KRASG12C.Our degrader series based on a non-covalent inhibitor and a ligand that recruits VHL successfully engaged VHL in cells, bound KRASG12C in vitro, induced VHL/ KRASG12C dimerization, and degraded KRASG12C in cells in a VHL-dependent manner. The representative compound induced KRASG12C ubiquitination and degradation with the DC50 value of 0.1 μM and Dmax value of 90%. Its discovered that the PROTAC degrader, the structure of the linker plays a key role in inducing degradation of the target protein.
This current study demonstrated that conformational restriction of the linker in PROTAC KRASG12C degraders, coupled with modifications of KRASG12 binder portion are critical in the finding of potent KRASG12C degraders.
Legal entity responsible for the study
Has not received any funding.
All authors have declared no conflicts of interest.