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 [IC 50 ] = 4.97 and 9.88 μM, respectively), Pan02 (IC 50  = 4.36 and 2.50 μM, respectively), and HGC-27 (IC 50  = 4.36 and 2.50 μM, 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.