Discovery of pyrrolo[3,2-c]quinoline-4-one derivatives as novel hedgehog signaling inhibitors.
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.
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. tomohiro.oohashi@takeda.com
Tomohiro
T
Ohashi
Yuya
Y
Oguro
Toshio
T
Tanaka
Zenyu
Z
Shiokawa
Sachio
S
Shibata
Yoshihiko
Y
Sato
Hiroko
H
Yamakawa
Harumi
H
Hattori
Yukiko
Y
Yamamoto
Shigeru
S
Kondo
Maki
M
Miyamoto
Hideaki
H
Tojo
Atsuo
A
Baba
Satoshi
S
Sasaki
D042462:4-Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008527:Medulloblastoma / Q000188:drug therapy*; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014184:Transplantation, Homologous; D000071676:Zinc Finger Protein GLI1
D042462:4-Quinolones; D000970:Antineoplastic Agents; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; D000071676:Zinc Finger Protein GLI1; C561669:pyrrolo(3,2-c)quinolin-4-one