Inauhzin analogues that induce P53, inhibit cell growth, and have antitumor activity

US9447103B2 · kind B2 · utility

Assignee

• INDIANA UNIVERSITY RESEARCH AND TECHNOLOGY CORPORATION · US

Inventors

• Hau Lu · Metairie, US
• Shelya Zeng · Metairie, US
• Qi Zhang · Beijing, CN
• Qizhuang Ye · Carmel, US
• Derong Ding · South Bend, US

Key dates

• Filing date: Jul 27, 2013
• Grant date: Sep 20, 2016
• Expiry date: Jul 27, 2033

Classification

• Technology area (CPC C): Chemistry; Metallurgy
• CPC primary: C07D519/00
• WIPO field: Pharmaceuticals
• WIPO sector: Chemistry

Abstract

Inauhzin (INZ) was identified as a novel p53 activator, which selectively and efficiently suppressing tumor growth without displaying genotoxicity and with little toxicity to normal cells. A panel of INZ analogs were synthesized and evaluated their ability to induce cellular p53 and to inhibit cell growth in cell-based assays. As described, this leads to the discovery of INZ analog 37, a molecule that exhibits much better potency than INZ in both of p53 activation and cell growth inhibition in several human cancer cell lines including H460 and HCT116+/+ cells. This INZ analog exhibited a much lower effect on p53-null H1299 cells and importantly no toxicity towards normal human p53-containing WI-38 cells. Those results also reveal key chemical features for INZ activity, and identify the newly synthesized INZ analog 37 as a better small molecule for further development of anti-cancer therapies.