Abstract
Aberrant activation of the Hedgehog (Hh) signaling pathway has been observed in various human malignancies. Glioma-associated oncogene transcription factor 1 (GLI1) is the ultimate effector of the canonical Hh pathway and has also been identified as a common regulator of several tumorigenic pathways prevalent in Hh-independent cancers. The anti-cancer potential of GLI1 antagonism with small molecule inhibitors has demonstrated initial promise; however, the continued development of GLI1 inhibitors is still needed. We previously identified a scaffold containing an 8-hydroxyquinoline as a promising lead GLI1 inhibitor (compound 1). To further develop this scaffold, we performed a systematic structure–activity relationship study to map the structural requirements of GLI1 inhibition by this chemotype. A series of biophysical and cellular experiments identified compound 39 as an enhanced GLI1 inhibitor with improved activity. In addition, our studies on this scaffold suggest a potential role for SRC family kinases in regulating oncogenic GLI1 transcriptional activity.
Original language | English (US) |
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Article number | 106387 |
Journal | Bioorganic Chemistry |
Volume | 132 |
DOIs | |
State | Published - Mar 2023 |
Externally published | Yes |
Keywords
- 8-Hydroxyquinoline
- GLI1 inhibitor
- Hedgehog pathway
- Src kinase
- Structure-based drug design
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Drug Discovery
- Organic Chemistry