The efficacy and mechanism of the novel small molecule degradation agent LS-13 targeting ARfl/ARv7 to inhibit enzalutamide resistant in prostate cancer

Enzalutamide resistance (ENZR) is the most common issue in castration-resistant prostate cancer (CRPC). After a period of treatment with the second-generation androgen receptor (AR) inhibitor enzalutamide (ENZ), patients develop resistance to ENZ, posing a serious threat to male health. However, there are currently no effective drugs for treating prostate cancer patients with ENZ resistance. Based on the structural optimization and modification of enzalutamide, and through molecular biological methods such as cell viability assays, colony formation, cell apoptosis detection, Western blot and other molecular biology techniques, it was discovered that the half-maximal inhibitory concentration values of LS-13 for prostate cancer LNCaP-ENZR and 22RV1 cells are 17.09 and 19.90 μmol·L^-1, respectively. Subsequently, after treating the resistant cell lines with 0.1, 1, 5, and 10 μmol·L^-1 of LS-13 for 12 days, the observation results indicated that LS-13 could inhibit the in vitro clonal formation of LNCaP-ENZR and 22RV1 cells in a dose-dependent manner. Furthermore, after treating the resistant cell lines with 1.25, 2.5, 5, and 10 μmol·L^-1 of LS-13 for 72 h, the results of flow cytometry also showed that LS-13 could promote apoptosis of the resistant cell lines in a dose-dependent manner. Furthermore, under the same concentration conditions described above, after LS-13 treatment of 22RV1 cells for 24 h, it was found that their migration speed was significantly slowed down (P < 0.05). These results collectively indicate that the small molecule compound LS-13 has a pronounced effect in inhibiting ENZR. Further mechanism studies found that LS-13 can target ARfl/ARv7 and promote its protein degradation, inhibit the transcription levels of AR-downstream target genes, thereby suppressing ENZR cell proliferation and promoting apoptosis. This study provides a candidate compound for targeting ARfl/ARv7 to overcome ENZ resistance.