4.7 Article

HSF1 Pathway Inhibitor Clinical Candidate (CCT361814/NXP800) Developed from a Phenotypic Screen as a Potential Treatment for Refractory Ovarian Cancer and Other Malignancies

期刊

JOURNAL OF MEDICINAL CHEMISTRY
卷 66, 期 8, 页码 5907-5936

出版社

AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.3c00156

关键词

-

向作者/读者索取更多资源

CCT251236, a potent chemical probe, was developed through a cell-based high-throughput screen to discover inhibitors of the transcription factor HSF1 that supports malignancy. The compound was optimized to mitigate P-glycoprotein efflux and eventually led to the design of a clinical candidate, CCT361814/NXP800 22, which demonstrated tumor regression in a human ovarian adenocarcinoma xenograft model. It has now progressed to phase 1 clinical trial as a potential treatment for refractory ovarian cancer and other malignancies.
CCT251236 1, a potent chemical probe, was previously developed from a cell-based phenotypic high-throughput screen (HTS) to discover inhibitors of transcription mediated by HSF1, a transcription factor that supports malignancy. Owing to its activity against models of refractory human ovarian cancer, 1 was progressed into lead optimization. The reduction of P-glycoprotein efflux became a focus of early compound optimization; central ring halogen substitution was demonstrated by matched molecular pair analysis to be an effective strategy to mitigate this liability. Further multiparameter optimization led to the design of the clinical candidate, CCT361814/NXP800 22, a potent and orally bioavailable fluorobisamide, which caused tumor regression in a human ovarian adenocarcinoma xenograft model with on-pathway biomarker modulation and a clean in vitro safety profile. Following its favorable dose prediction to human, 22 has now progressed to phase 1 clinical trial as a potential future treatment for refractory ovarian cancer and other malignancies.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.7
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据