Structure-activity relationship studies on Pd176252 derivatives leading to discovery of novel GRP receptor antagonist with potent anticancer activity

Gastrin-releasing peptide (GRP)/gastrin-releasing peptide receptor (GRPR) have various physiological effects, and many studies report that GRPR is a potential anticancer target. Pd176252 is a typical small-molecule GRPR antagonist that exhibits anti-proliferation activity against most cancers. In this study, 31 novel Pd176252 analogues were designed, synthesized, and evaluated for anti-proliferation activity against human prostate cancer (PC3), mouse pancreatic cancer (Pan02), human gastric cancer (HGC-27), and hepatocellular carcinoma (HepG2) cell lines. Of all the compounds evaluated, 5a and 6e showed better anti-proliferation activity compared to Pd176252 against PC3 (half-maximal inhibitory concentration [IC50]= 4.97 and 9.88 mu M, respectively), Pan02 (IC50 = 4.36 and 2.50 mu M, respectively), and HGC-27 (IC50 = 4.36 and 2.50 mu M, respectively), cell lines. Moreover, combining 5a or 6e with a histone deacetylase (HDAC) inhibitor further improved the in vitro anti-proliferation activity. Further research showed that 5a caused HGC-27 cell apoptosis by downregulating Bcl-2 and upregulating Bax. In addition, a molecular docking analysis showed that compounds 5a and 6e could bind to GRPR. In conclusion, compounds 5a and 6e are novel GRPR antagonists with potent anticancer activity.

Automated summary

Novel Pd176252 analogues, specifically 5a and 6e, showed better anti-proliferation activity against various cancer cell lines compared to Pd176252, with potential synergistic effects when combined with a histone deacetylase inhibitor. These compounds exhibit potent anticancer activity by inducing apoptosis and binding to GRPR.