Balance-Based Drug Discovery Laboratory, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
J Med Chem. 2024 Jan 25;67(2):1481-1499. doi: 10.1021/acs.jmedchem.3c02063. Epub 2024 Jan 16.
Nuclear receptor receptor-related orphan receptor γ (RORγ) is a ligand-dependent transcription factor and has been established as a key player in castration-resistant prostate cancers (CRPC) by driving androgen receptor (AR) overexpression, representing a potential therapeutical target for advanced prostate cancers. Here, we report the identification of the first-in-class RORγ covalent inhibitor via the structure-based drug design approach following structure-activity relationship (SAR) exploration. Mass spectrometry assay validated its covalent inhibition mechanism. Compound significantly inhibited RORγ transcriptional activity and remarkably suppressed the expression levels of AR and AR-targeted genes. Compound also exhibited much superior activity in inhibiting the proliferation and colony formation and inducing apoptosis of the CRPC cell lines relative to the positive control and noncovalent control . Importantly, it markedly suppressed the tumor growth in a 22Rv1 mouse tumor xenograft model with good safety. These results clearly demonstrate that is a highly potent and selective RORγ covalent inhibitor.
核受体相关孤儿受体 γ（RORγ）是一种配体依赖性转录因子，通过驱动雄激素受体（AR）过表达，已被确立为去势抵抗性前列腺癌（CRPC）的关键因子，代表了晚期前列腺癌潜在的治疗靶点。在这里，我们通过结构活性关系（SAR）探索，基于结构的药物设计方法，报告了首例 RORγ 共价抑制剂的鉴定。质谱分析验证了其共价抑制机制。化合物显著抑制了 RORγ 的转录活性，并显著抑制了 AR 和 AR 靶向基因的表达水平。与阳性对照和非共价对照相比，化合物在抑制 CRPC 细胞系的增殖、集落形成和诱导细胞凋亡方面表现出更高的活性。重要的是，它在 22Rv1 小鼠肿瘤异种移植模型中显著抑制肿瘤生长，且安全性良好。这些结果清楚地表明，是一种高效且选择性的 RORγ 共价抑制剂。
