6304-89-8Relevant articles and documents
Structure-Activity Study of Nitazoxanide Derivatives as Novel STAT3 Pathway Inhibitors
Lü, Zirui,Li, Xiaona,Li, Kebin,Wang, Cong,Du, Tingting,Huang, Wei,Ji, Ming,Li, Changhong,Xu, Fengrong,Xu, Ping,Niu, Yan
supporting information, p. 696 - 703 (2021/05/04)
We identified nitazoxanide (NTZ) as a moderate STAT3 pathway inhibitor through immunoblot analysis and a cell-based IL-6/JAK/STAT3 pathway activation assay. A series of thiazolide derivatives were designed and synthesized to further validate the thiazolide scaffold as STAT3 inhibitors. Eight out of 25 derivatives displayed potencies greater than that of NTZ, and their STAT3 pathway inhibitory activities were found to be significantly correlated with their antiproliferative activities in HeLa cells. Derivatives 15 and 24 were observed to be more potent than the positive control WP1066, which is under phase I clinical trials. Compared with NTZ, 15 also exhibited much improved in vivo pharmacokinetic parameters in rats and efficacies against proliferations in multiple cancer cell lines, indicating a broad-spectrum effect of these thiazolides as antitumor agents targeted on STAT3.
Discovery of 4-methyl-N-(4-((4-methylpiperazin- 1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-oxy)benzamide as a potent inhibitor of RET and its gatekeeper mutant
Chen, Guyue,Deng, Xianming,Deng, Zhou,Dong, Chao,Hu, Zhiyu,Li, Li,Li, Xiaoyang,Lian, Wenhua,Liu, Xueyan,Su, Jingyi,Wang, Zheng,Xu, Qingyan,Yang, Yanru,Yang, Zaiyou,Zhang, Baoding
, (2020/09/02)
The receptor tyrosine kinase rearranged during transfection (RET) plays pivotal roles in several cancers, including thyroid carcinoma and non-small cell lung cancer (NSCLC). Currently, there are several FDA-approved RET inhibitors, but their indication is limited to thyroid cancer, and none can overcome their gatekeeper mutants (V804L and V804M). Here, we report the discovery of 9x representing a new chemotype of potent and selective RET inhibitors, using a rational design strategy of type II kinase inhibitors. 9x exhibited both superior antiproliferative activities against NSCLC-related carcinogenic fusions KIF5B-RET and CCDC6-RET and gatekeeper mutant-transformed Ba/F3 cells, with the lowest GI50 of 9 nM, and substantial inhibitory activities against wild-type RET and RET mutant proteins, with the best IC50 of 4 nM. More importantly, 9x also showed nanomole potency against RET-positive NSCLC cells LC-2/ad, but not against a panel of RET-negative cancer cells, such as A549, H3122, A375 or parental Ba/F3 cells, demonstrating its selective ‘on-target’ effect. In mouse xenograft models, 9x repressed tumor growth driven by both wild type KIF5B-RET-Ba/F3 and gatekeeper mutant KIF5B-RET(V804M)-Ba/F3 cells in a dose-dependent manner. Together, these data establish that 9x provides a good starting point for the development of targeted therapeutics against RET-positive cancers, especially NSCLC.
Aspirin-inspired acetyl-donating HDACs inhibitors
Lim, Jiah,Song, Yoojin,Jang, Jung-Hee,Jeong, Chul-Ho,Lee, Sooyeun,Park, Byoungduck,Seo, Young Ho
, p. 967 - 976 (2018/06/25)
Aspirin is one of the oldest drugs for the treatment of inflammation, fever, and pain. It is reported to covalently modify COX-2 enzyme by acetylating a serine amino acid residue. By virtue of aspirin’s acetylating potential, we for the first time developed novel acetyl-donating HDAC inhibitors. In this study, we report the design, synthesis, in silico docking study, and biological evaluation of acetyl-donating HDAC inhibitors. The exposure of MDA-MB-231 cells with compound 4c significantly promotes the acetylation of α-tubulin and histone H3, which are substrates of HDAC6 and HDAC1, respectively. In silico docking simulation also indicates that compound 4c tightly binds to the deep substrate-binding pocket of HDAC6 by coordinating the active zinc ion in a bidentate manner and forming hydrogen bond interactions with Ser531 and His573 amino acid residues. In particular, compound 4c (GI50 = 147?μM) affords the significant enhancement of anti-proliferative effect on MDA-MB-231 cells, compared with its parent compound 2c (GI50 > 1000?μM) and acetyl-donating group deficient compound 6 (GI50 = 554?μM). Overall, compound 4c presents a novel strategy for developing acetyl-donating HDAC inhibitors.
