440P - Targeting KRAS^G12C: Repurposing of potential therapeutics for the treatment of pancreatic ductal adenocarcinoma (PDAC)

Background

Pancreatic ductal adenocarcinoma (PDAC), accounting for more than 90% of all pancreatic malignancies, and the fourth most frequent cause of cancer-related mortalities worldwide with a 5-year overall survival of less than 8%. The main molecular trait of this deadly disease is the MAPK pathway activation due to KRAS mutation. The KRAS^G12C, an oncogenic driver mutation in PDAC, was studied to identify potential therapeutic candidates.

Methods

Molecular docking of more than 500 FDA approved drugs and the KRAS^G12C-reference drug (Adagrasib) with the protein KRAS^G12C (RCSB ID:5F2E) was performed followed by superimposition of drugs having the highest binding affinities. The predicted ligand binding site of the mutated KRAS was determined. Subsequently, the drug-protein interactions were visualized Finally, the pharmacokinetic properties of the reference and selected candidates were assessed to suggest the most promising drug candidate for PDAC.

Results

The reference drug Adagrasib had a binding affinity of -10 kcal/mol. Among the drugs taken in the study, Apalutamide, an androgen receptor (AR) antagonist, showed a high binding affinity of -10.4 kcal/mol, and had six common amino acids with the KRAS^G12C reference. It further interacted with the amino acids that formed the binding site of KRAS. This suggests that it may bind to the protein’s ligand-binding site to produce an inhibitory effect. Apalutamide also showed excellent GI absorption (90.7%), and intestinal permeability compared to the reference; it did not penetrate the CNS or the blood brain barrier as suggested by the CNS, logBB and PSA values of -1, -0.898 and 113.2, respectively.

Conclusions

The study provides evidence that Apalutamide could be considered a potential therapeutic agent for KRAS^G12C in the effective treatment of PDAC. However, future studies in in vitro as well as in vivo models should elucidate the safety and efficacy of Apalutamide in PDAC.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

BRAC University.

Disclosure

All authors have declared no conflicts of interest.