Discovery of pyrrolo[3,2-c]quinoline-4-one derivatives as novel hedgehog signaling inhibitors

详细信息    查看全文

• 作者：Tomohiro Ohashi ; Yuya Oguro ; Toshio Tanaka ; Zenyu Shiokawa ; Sachio Shibata ; Yoshihiko Sato ; Hiroko Yamakawa ; Harumi Hattori ; Yukiko Yamamoto ; Shigeru Kondo ; Maki Miyamoto ; Hideaki Tojo ; Atsuo Baba ; Satoshi Sasaki
• 关键词：Hedgehog ; Hh signaling inhibitor ; Pyrrolo[3 ; 2-c]quinoline-4-one
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 出版时间：15 September, 2012
• 年：2012
• 卷：20
• 期：18
• 页码：5496-5506
• 全文大小：777 K

文摘

The Hedgehog (Hh) signaling pathway plays a significant role in the regulation of cell growth and differentiation during embryonic development. Since activation of the Hh signaling pathway is implicated in several types of human cancers, inhibitors of this pathway could be promising anticancer agents. Using high throughput screening, thieno[3,2-c]quinoline-4-one derivative 9a was identified as a compound of interest with potent in vitro activity but poor metabolic stability. Our efforts focused on enhancement of in vitro inhibitory activity and metabolic stability, including core ring conversion and side chain optimization. This led to the discovery of pyrrolo[3,2-c]quinoline-4-one derivative 12b, which has a structure distinct from previously reported Hh signaling inhibitors. Compound 12b suppressed stromal Gli1 mRNA expression in a murine model and demonstrated antitumor activity in a murine medulloblastoma allograft model.