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

Abstract

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.

• Authors: 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
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 20 Issue 18 Pg. 5496-506 (Sep 15 2012) ISSN: 1464-3391 [Electronic] England
• PMID: 22910224 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• 4-Quinolones
• Antineoplastic Agents
• Gli1 protein, mouse
• Hedgehog Proteins
• Kruppel-Like Transcription Factors
• RNA, Messenger
• Zinc Finger Protein GLI1
• pyrrolo(3,2-c)quinolin-4-one

Topics

• 4-Quinolones (chemical synthesis, chemistry, pharmacology)
• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Discovery
• Hedgehog Proteins (antagonists & inhibitors, metabolism)
• High-Throughput Screening Assays
• Humans
• Kruppel-Like Transcription Factors (antagonists & inhibitors, genetics, metabolism)
• Medulloblastoma (drug therapy)
• Mice
• Mice, Knockout
• Models, Molecular
• Molecular Structure
• NIH 3T3 Cells
• RNA, Messenger (antagonists & inhibitors, genetics)
• Signal Transduction (drug effects)
• Structure-Activity Relationship
• Transplantation, Homologous
• Zinc Finger Protein GLI1