Elektrooptik

Eintrag vom: 24.09.2013.

ACBI3 a PROTAC-based degrader works by tagging the mutant KRAS proteins for degradation offering a novel approach compared to traditional KRAS inhibitors that only target the G12C mutation.

 

In my preliminary studies I found that KRAS degradation in PDAC organoids leads to marked changes in the immunopeptidome with enrichment of peptides derived from ER-resident and stress-associated proteins.

 

A comprehensive overview of the chemical structure properties and mechanism of action of ACBI3 a first-in-class PROTAC selectively targeting oncogenic KRAS mutants.

 

Experts have developed a breakthrough small-molecule drug a 'protein degrader'. This molecule called ACBI3 could potentially lead to new therapies independent of KRAS mutation type ...

 

To develop a KRAS PROTAC capable of degrading the most common oncogenic KRAS mutants the authors designed a heterobifunctional small molecule that links KRAS mutant proteins and the VHL E3...

 

Binding of ACBI3 to KRAS was demonstrated in the surface plasmon resonance assay with KRASG12D GDP (KD = 5 ± 1 nM; n = 3) and KRASG12V GDP (KD = 4 ± 1 nM; n = 3) and in the fluorescence polarization assay with VCB+KRASG12D (KD = 4 ± 1 nM; n = 3).

 

ACBI3 achieves in vivo degradation of oncogenic KRAS resulting in durable pathway modulation and tumor regressions in KRAS mutant xenograft mouse models. For research use only. We do not sell to patients.

 

ACBI3 is a first in class VHL-recruiting PROTAC molecule potently degrading multiple KRAS variants in vitro and in vivo. Proteolytic degradation of KRAS via ACBI3 enables a greater than 10-fold higher potency compared to target inhibition and results in prolonged suppression of MAPK signaling.

 

ACBI3 is a selective potent and in vivo active pan-KRAS degrader discovered by means of a structure-based design approach guided by optimization of VHL:PROTAC:KRAS ternary complex stability and durability.