Discovery of benzenesulfonamide derivatives as potent PI3K/mTOR dual inhibitors with in vivo efficacies against hepatocellular carcinoma

• Published in: Bioorganic & medicinal chemistry Vol. 24; no. 5; pp. 957 - 966
• Main Authors: Chen, Ying, Zhang, Ling, Yang, Chao, Han, Jinsong, Wang, Chongqing, Zheng, Canhui, Zhou, Youjun, Lv, Jiaguo, Song, Yunlong, Zhu, Ju
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.03.2016; Elsevier
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antitumor; Benzenesulfonamide derivatives; Benzenesulfonamides; Biochemistry & Molecular Biology; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dual inhibitors; Hepatocellular carcinoma; Humans; Life Sciences & Biomedicine; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; Mammalian target of rapamycin (mTOR); Mice, Inbred BALB C; Mice, Nude; Pharmacology & Pharmacy; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide 3-kinase (PI3K); Phosphoinositide-3 Kinase Inhibitors; Physical Sciences; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Science & Technology; Signal Transduction - drug effects; Sulfonamides - chemistry; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; FoxO; HCC; Hepatocellular carcinoma; AKT; MTT; Benzenesulfonamide derivatives; Mammalian target of rapamycin (mTOR); BBRINJUWZRLWKK-UHFFFAOYSA-N; CREB; PI3K; Dual inhibitors; IC50; Antitumor; mTOR; PIP3; Phosphoinositide 3-kinase (PI3K); GI50; PIP2; MAMMALIAN TARGET; CANCER-CELLS; RAPAMYCIN; NVP-BEZ235; PROLIFERATION; SORAFENIB; PATHWAY; GROWTH; DIFFERENTIATION
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.01.008

[Display omitted] The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is related to cellular activities. Abnormalities of this signaling pathway were discovered in various cancers, including hepatocellular carcinoma (HCC). The PI3K/mTOR dual inhibitors were proposed to have enhanced antitumor efficacies by targeting multiple points of the signaling pathway. We synthesized a series of propynyl-substituted benzenesulfonamide derivatives as PI3K/mTOR dual inhibitors. Compound 7k (NSC781406) was identified as a highly potent dual inhibitor, which exhibited potent tumor growth inhibition in the hepatocellular carcinoma BEL-7404 xenograft model. Compound 7k may be a potential therapeutic drug candidate for HCC.