Discovery of the First-in-Class RORγ Covalent Inhibitors for Treatment of Castration-Resistant Prostate Cancer.
Wei FangJianwei ZhengLin DengYana AnDeqin RongJianwei WeiXiao-Feng XiongJunjian WangYuanxiang WangPublished in: Journal of medicinal chemistry (2024)
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 29 via the structure-based drug design approach following structure-activity relationship (SAR) exploration. Mass spectrometry assay validated its covalent inhibition mechanism. Compound 29 significantly inhibited RORγ transcriptional activity and remarkably suppressed the expression levels of AR and AR-targeted genes. Compound 29 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 2 and noncovalent control 33 . Importantly, it markedly suppressed the tumor growth in a 22Rv1 mouse tumor xenograft model with good safety. These results clearly demonstrate that 29 is a highly potent and selective RORγ covalent inhibitor.
Keyphrases
- transcription factor
- prostate cancer
- mass spectrometry
- structure activity relationship
- high throughput
- binding protein
- oxidative stress
- cell proliferation
- small molecule
- cell death
- genome wide
- emergency department
- cancer therapy
- cell cycle arrest
- risk assessment
- drug induced
- dna binding
- genome wide identification
- human health
- young adults
- combination therapy
- gas chromatography
- drug delivery
- dna methylation
- ms ms
- heat shock protein
- adverse drug
- capillary electrophoresis
- heat shock