1174569-49-3Relevant academic research and scientific papers
Pharmacokinetic optimization of class-selective histone deacetylase inhibitors and identification of associated candidate predictive biomarkers of hepatocellular carcinoma tumor response
Wong, Jason C.,Tang, Guozhi,Wu, Xihan,Liang, Chungen,Zhang, Zhenshan,Guo, Lei,Peng, Zhenghong,Zhang, Weixing,Lin, Xianfeng,Wang, Zhanguo,Mei, Jianghua,Chen, Junli,Pan, Song,Zhang, Nan,Liu, Yongfu,Zhou, Mingwei,Feng, Lichun,Zhao, Weili,Li, Shijie,Zhang, Chao,Zhang, Meifang,Rong, Yiping,Jin, Tai-Guang,Zhang, Xiongwen,Ren, Shuang,Ji, Ying,Zhao, Rong,She, Jin,Ren, Yi,He, Yun,Chen, Li,Xu, Chunping,Chen, Dawei,Cai, Jie,Chen, Taiping,Shan, Song,Pan, Desi,Ning, Zhiqiang,Lu, Xianping
, p. 8903 - 8925,23 (2020/09/16)
Herein, we describe the pharmacokinetic optimization of a series of class-selective histone deacetylase (HDAC) inhibitors and the subsequent identification of candidate predictive biomarkers of hepatocellular carcinoma (HCC) tumor response for our clinical lead using patient-derived HCC tumor xenograft models. Through a combination of conformational constraint and scaffold hopping, we lowered the in vivo clearance (CL) and significantly improved the bioavailability (F) and exposure (AUC) of our HDAC inhibitors while maintaining selectivity toward the class I HDAC family with particular potency against HDAC1, resulting in clinical lead 5 (HDAC1 IC50 = 60 nM, mouse CL = 39 mL/min/kg, mouse F = 100%, mouse AUC after single oral dose at 10 mg/kg = 6316 h·ng/mL). We then evaluated 5 in a biomarker discovery pilot study using patient-derived tumor xenograft models, wherein two out of the three models responded to treatment. By comparing tumor response status to compound tumor exposure, induction of acetylated histone H3, candidate gene expression changes, and promoter DNA methylation status from all three models at various time points, we identified preliminary candidate response prediction biomarkers that warrant further validation in a larger cohort of patient-derived tumor models and through confirmatory functional studies.
NOVEL N-(2-AMINO-PHENYL)-AMIDE DERIVATIVES
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Page/Page column 9, (2009/08/18)
The present invention provides novel compounds of the general formula (I) and pharmaceutically acceptable salts thereof, processes for the manufacture of these novel compounds and medicaments containing such compounds. The compounds of the present inventi
NOVEL N-(2-AMINO-PHENYL)-ACRYLAMIDES
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Page/Page column 7, (2009/12/05)
The present invention is directed to the compounds of formula wherein R1 to R4 have the significances given herein, to processes for the manufacture of said compounds as well as medicaments containing said compounds. The compounds ac
