OBJECTIVE To evaluate the anticancer activity of andrographolide(AGP)and its semisynthetic analogues(SRJ09and SRJ23)in pancreatic adenocarcinoma(PDAC)cell lines harbouring therapeutically highly relevant oncogenic K-ras glycine-12(KRAS-G12)mutant proteins.In a landmark publication,we revealed that AGP and its derivatives bind KRAS protein to inhibit RAS signaling PNAS,110:10201-06).This discovery prompted the initiation of this investigation.METHODS The cell growth inhibitory effect of the compounds on PDAC cell lines〔PANC-1(KRAS-G12D),Capan-2(KRAS-G12V),and MIA PaCa-2(KRASG12C)〕,was assessed by MTT assay.RESULTS In comparison with AGP and SRJ09,SRJ23 showed the greatest growth inhibition in all PDAC cell lines with mutant KRAS proteins.The inhibitory effect of SRJ23 on the cell growth was similar for all PDAC cell lines.AGP exerted selective growth inhibition against PANC-1(KRAS-G12D)cells,while the growth inhibition of SRJ09 was selective towards Capan-2(KRAS-G12V)cells.CONCLUSION AGP and SRJ09 showed selectivity for PDAC cell lines with specific KRAS mutations.This suggests the mutational status of KRAS protein and the structural features of these two compounds orchestrally determined the magnitude of cell growth inhibition in PDAC cell lines.The higher potency of SRJ23 implies it could be developed into an anticancer agent for the treatment of mutant KRAS-driven malignancies.To this end,efforts are in progress to derive new molecules from this compound for further improvement of potency. OBJECTIVE To evaluate the anticancer activity of andrographolide (AGP) and its semisynthetic analogues (SRJ09 and SRJ23) in pancreatic adenocarcinoma (PDAC) cell lines harboring therapeutically highly relevant oncogenic K-ras glycine-12 (KRAS-G12) , we revealed that AGP and its derivatives bind KRAS protein to inhibit RAS signaling PNAS, 110: 10201-06). This discovery suggests the initiation of this investigation. METHODS The cell growth inhibitory effect of the compounds on PDAC cell lines [PANC-I (KRAS-G12D), Capan-2 (KRAS-G12V), and MIA PaCa-2 (KRASG12C)], was assessed by MTT assay.RESULTS In comparison with the AGP and SRJ09, SRJ23 showed the greatest growth inhibition in all PDAC cell lines with mutant KRAS proteins. The inhibitory effect of SRJ23 on the cell growth was similar for all PDAC cell lines. AGP exerted selective growth inhibition against PANC-1 (KRAS-G12D) cells, while the growth inhibition of SRJ09 was selective towards Capan-2 (KRAS-G12V) cells.CONCLUSIO N AGP and SRJ09 showed selectivity for PDAC cell lines with specific KRAS mutations. This suggests the mutational status of KRAS protein and the structural features of these two compounds orchestrally determined the magnitude of cell growth inhibition in PDAC cell lines. Higher potency of SRJ23 implies it could be developed into an anticancer agent for the treatment of mutant KRAS-driven malignancies. To this end, efforts are in progress to derive new molecules from this compound for further improvement of potency.