Targeting K-ras with semisynthetic andrographolide derivatives:A valid approach in the discovery of potential anticancer drug leads

We embarked on the discovery of anticancer agents from andrographolide nearly 15 years ago.Thus far,a few lead semisynthetic compounds have been identified,but only recently we managed to pinpoint their potential molecular target.Through in silico and cell-based studies,these lead molecules have been found to bind K-ras oncoprotein and disrupt its function.Further molecular docking analysis suggested the compounds targeted both wild-type and oncogenic mutant K-ras.However,the binding affinity was greater for the oncogenic protein.Low binding energies to wild-type K-ras protein suggested transient binding and inhibition.The compounds showed stronger binding interactions to all three mutant K-ras proteins(G12V,G12 Cand G12D)with average free energies(ΔG bind)of-82kcal·mol-1 as compared with-61kcal·mol-1 for the wild-type protein.It is noteworthy that the binding pocket in wild-type K-ras protein,however,is different from that of the mutant proteins.SRJ23,one of the lead compounds,showed the strongest binding interactions to all three mutant K-ras proteins.Stronger binding to the mutant proteins could lead to more targeted and prolonged inhibition.Investigation into the effect of the compounds on RAS-MAPK pathway showed this pathway was disrupted in colon,breast and prostate cancer cells.In vivo studies revealed the compounds retarded the growth of human colon(HCT-116)and prostate(PC-3)cancer xenografts in mice.All of the above prompted us to synthesise derivatives of the lead compounds for improvement of binding affinity for the oncogenic K-ras.A preliminary in silico exploration found some compounds with such property and these compounds are presently undergoing extensive pharmacological investigations.