Discovery of novel oleanolic acid glycoside derivatives targeting PTP1B/PI3K/AKT signaling pathway for the treatment of breast cancer

Protein tyrosine Phosphatase 1B (PTP1B) has been identified as a key drug target for anti-tumor drug development. Oleanolic acid (OA) has been proved to be an inhibitor of PTP1B, but its poor water solubility, low bioavailability and poor activity in vivo limit its clinical efficacy. In this study, a total of 47 new OA derivatives including heteroatom derivatives, ester derivatives, amino substitution derivatives and Schiff base derivatives were designed and synthesized. Among them, OA-Br-1 had stronger inhibition and selectivity on PTP1B than OA, with IC₅₀ value of 7.08 ± 5.05 μM for PTP1B and 222.28 ± 0.11 μM for TCPTP. In addition, OA-Br-1 significantly inhibited the proliferation and induced Apoptosis of breast Cancer cells, and in vivo nude mice experiments also showed that OA-Br-1 could inhibit the growth of breast tumors. Then network pharmacology was used to predict the targets of OA-Br-1, and the PPI network map between compound - breast Cancer - target was constructed. The results showed that the probability value of PTPN1 ranked first among all predicted targets, which was consistent with the results of Enzyme activity experiments in vitro. The enrichment results of KEGG pathway and GO functional annotation analysis showed that the effect of OA-Br-1 on breast Cancer was significantly correlated with the PI3K/Akt pathway. Subsequent Western Blot results also proved that OA-Br-1 could significantly inhibit the expression of PTP1B, p-PI3K and p-AKT, indicating that OA-Br-1 played an anti-breast Cancer role through the PTP1B/PI3K/Akt signaling pathway. Collectively, these findings identify OA-Br-1 as a promising PTP1B inhibitor for breast Cancer treatment.

Breast cancer; Oleanolic acid; PI3K/AKT; PTP1B.