We previously identified that 1-(2-Nitrovinyl)naphthalene (Z-10) is a ligand of retinoid x receptor α (RXRα) with a potent anti-breast cancer efficacy and revealed that nitro group is an essential pharmacophore in Z-10. In this study, we defined that the double bond of the nitrovinyl group is also vital for Z-10 to bind and activate RXRα. Mechanistically, the double bond has a chemical ability to mediate Z-10's covalent binding of RXRα via the Michael addition reaction with Cys432. By retaining the nitrovinyl group, a series of Z-10 analogues with different aromatic groups and different aromatic ring-positions of nitrovinyl group and alkoxy groups were designed and synthesized. We found that some analogues including compound 30 show stronger ability than Z-10 in inhibiting TNFα survival signal in MDA-MB-231 breast cancer cells. Interestingly, these RXRα ligands also bind to tubulins likely through the similar covalent interaction and induce the degradation of tubulins and cell cycle arrest in MDA-MB-231 cells, of which 30 displays the strongest efficacy. Importantly, these analogues and TNFα exhibit synergistic effects in inducing breast cancer cell apoptosis, of which 30 shows greater efficacy than Z-10. Together, our study provides a theoretical basis for the RXRα and tubulin dual-targeting drug design for breast cancer treatment.

2025-02-13·Journal of Medicinal Chemistry

Discovery of N-(1,2,4-Thiadiazol-5-yl)benzo[b]oxepine-4-carboxamide Derivatives as Novel Antiresistance Androgen Receptor Antagonists

Article

作者: Pan, Peichen ; Shan, Luhu ; Fu, Weitao ; Xu, Xiaohong ; Wang, Huating ; Liao, Jianing ; Hou, Tingjun ; Sheng, Rong ; Xu, Lei ; Chai, Xin ; Wang, Xinyue ; Li, Dan ; Wang, Ying ; Liao, Jinbiao

The ligand-binding pocket of the androgen receptor (AR) is the targeting site of all clinically used AR antagonists. However, various drug-resistant mutations emerged in the pocket. We previously reported a new targeting site at the dimer interface of AR (dimer interface pocket) and identified a novel antagonist M17-B15 that failed in oral administration. In this study, the head part of M17-B15 was substituted with divergent structures. Potent antagonist Z10 with benzo[b]oxepine was first identified. Subsequent structural optimization on the 2-oxopropyl moiety of Z10 generated the more powerful Y5 (IC₅₀ = 0.04 μM). Out of the ordinary, Y5 demonstrated dual mechanisms of action, antagonized AR by disrupting AR dimerization, and induced AR degradation via the ubiquitin-proteasome pathway. Furthermore, Y5 exhibited excellent activity against variant drug-resistant AR mutants comparable to recently approved darolutamide. Furthermore, Y5 effectively suppressed the tumor growth of the LNCaP xenograft via oral administration, providing a potential novel therapeutic for drug-resistant prostate cancer.

2024-04-01·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

Pyrazole derivative Z10 ameliorates acute pancreatitis by inhibiting the ERK/Ddt pathway

Article

作者: Pan, Jian ; Huang, Borong ; Li, Wanlian ; Lu, Xing ; Zeng, Wenying ; Xiao, Juan

Acute pancreatitis (AP) can lead to death; however, there is no specific treatment for AP. Screening of drugs for AP treatment is rarely performed. Compounds were screened in a primary pancreatic acinar cell and peritoneal macrophage coculture system. Compounds were used in vitro and in vivo. Compound targets were predicted and validated. Among the 18 nitrogen-containing heterocycles, Z10 was shown to decrease the cerulein plus lipopolysaccharide (CL)-induced secretion of both acinar digestive enzymes and macrophage cytokines. Z10 was also shown to ameliorate CL-induced or sodium taurocholate-induced AP in mice. Proteomics analysis and enzyme linked immunosorbent assay (ELISA) revealed that Z10 decreased the levels of D-dopachrome tautomerase (Ddt) within macrophages and those in the extracellular milieu under CL treatment. Z10 also decreased Ddt expression in AP mice. Moreover, exogenous Ddt induced cytokine and digestive enzyme secretion, which could be inhibited by Z10. Ddt knockdown inhibited CL-induced cytokine secretion. Medium from CL-treated macrophages induced the release of amylase by acinar cells, and Ddt knockdown medium decreased amylase secretion. The target of Z10 was predicted to be ERK2. Z10 increased the thermostability of ERK1/2 but not ERK1 K72A/ERK2 K52A. The docking poses of ERK1 and ERK2 with Z10 were similar. Z10 inhibited ERK1/2 phosphorylation, and Ddt levels and cytokines were regulated by ERK1/2 during AP. Additionally, Z10 could not further inhibit cytokines under ERK1/2 knockdown with CL. Thus, this study revealed that Z10-mediated ERK1/2 inhibition decreased Ddt expression and secretion by macrophages. Ddt inhibition decreased cytokine release and digestive enzyme secretion.

100 项与 Z-010 相关的药物交易

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