A New Smoothened Antagonist Bearing the Purine Scaffold Shows Antitumour Activity In Vitro and In Vivo
The Smoothened (SMO) receptor is the most druggable target in the Hedgehog (HH) pathway for anticancer compounds. However, SMO antagonists such as vismodegib rapidly develop drug resistance. In this study, new SMO antagonists having the versatile purine ring as a scaffold were designed, synthesised,...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-08-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/16/8372 |
| Summary: | The Smoothened (SMO) receptor is the most druggable target in the Hedgehog (HH) pathway for anticancer compounds. However, SMO antagonists such as vismodegib rapidly develop drug resistance. In this study, new SMO antagonists having the versatile purine ring as a scaffold were designed, synthesised, and biologically tested to provide an insight to their mechanism of action. Compound <b>4s</b> was the most active and the best inhibitor of cell growth and selectively cytotoxic to cancer cells. <b>4s</b> induced cell cycle arrest, apoptosis, a reduction in colony formation and downregulation of <i>PTCH</i> and <i>GLI1</i> expression. BODIPY-cyclopamine displacement assays confirmed <b>4s</b> is a SMO antagonist. In vivo, <b>4s</b> strongly inhibited tumour relapse and metastasis of melanoma cells in mice. In vitro, <b>4s</b> was more efficient than vismodegib to induce apoptosis in human cancer cells and that might be attributed to its dual ability to function as a SMO antagonist and apoptosis inducer. |
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| ISSN: | 1661-6596 1422-0067 |