Background: Cancer patients treated with targeted anti-cancer drug suffer from itch or pruritus. Itch or pruritus is an unpleasant sensation that brings about a negative impact on quality of life, and serious itch may lead to dose reduction and even discontinuation. Gastrin releasing
peptide receptor (GRPR) plays a critical role in itch, inflammation and cancer, and GRPR antagonist has obvious effect on cancer, inflammation and itch. The aim of this paper is to develop a new agent with anti-cancer and anti-itch activity. Methods: A series of GRPR antagonist PD176252
analogues (3a-3l) were designed and synthesized. Both anticancer and anti-itch activities were evaluated. Anti-cancer activity was evaluated in three human cancer cell lines in vitro, the anti-itch activity in evaluated with Kunming mice by intrathecal injection of chloroquine phosphate as
a modeling medium. And the cytotoxicity on normal cells was evaluated. Results: Of the tested compounds, compound 3i showed potently anti-cancer activity to all cancer cell lines tested with IC50 values of 10.5μM (lung), 11.6μM (breast) and 12.8μM (liver) respectively and it
also showed significant inhibition of the scratching behavior. Comparing with PD17625, compound 3i and 3g gave better inhibition activities against all cancer cell lines, compound 3b, 3c and 3i showed better anti-itch activity. The compound 3i is safe for normal breast and liver normal cells,
but it has high cytotoxicity on normal lung cell. Conclusion: The synthesized compounds have dual anti-cancer and anti-itch activity, so the development of drug with dual anti-tumor and anti-itch property is possible.
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.
Background: GRPR is over-expressed in cancer cells and is a potential drug target for the treatment of cancer. PD176252, as the most representative non-peptide inhibitor of GRPR, can inhibit the growth of cancer cells, but its low selectivity to cancer cells and normal cells limits
its further application. Objective: The aim of this study was to design and synthesize novel GRPR inhibitor with stronger anti-cancer activity and higher affinity with GRPR than the lead compound PD176252. Methods: A series of 1, 3, 4-oxadiazole derivatives as PD176252 analogues
(4a-4j, 6a-6q) were synthesized and their cytotoxic activity was investigated on four cancer lines with high expression of GRPR (gastric (HGC-27), colon (HCT- 116), prostate (PC-3), and lung (A549)) and one human cell line (gastric mucosal epithelial (GES-1)) by MTT assay. Flow cytometry analysis
and Western Blot were used to determine whether the compound induced programmed apoptosis of cancer cells. Competitive binding experiment was used to verify the affinity between GRPR and the optimal compound. Results: Compound 6m exhibited significant growth inhibition on all tested cancer
cell lines, especially gastric cancer cells (HGC-27 cellular IC50 0.37 ± 0.04μM). Also, the selectivity of 6m to HGC-27 was much higher than that of PD176252. Flow cytometric analysis and Western Blot proved that 6m significantly promoted the apoptosis of HGC-
27 cells. Moreover, competitive binding experiment confirmed the close binding of 6m with GRPR, which indicated 6m with a higher affinity than lead compound PD176252. Conclusion: Our results suggested that 6m, as a novel GRPR inhibitor, had a higher affinity with GRPR and potential anti-cancer
effect than PD176252, which can be used as a template for further optimization.
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