Multitarget hedgehog pathway inhibitors and uses thereof
Molecules of natural origin potentially capable of modulating the Hedgehog signaling pathway were selected in silico. For SMO antagonists, a ligand-based pharmacophoric approach was followed that focused on the chemical structure of some clinical trial SMO antagonists. Structure-based methods based on the crystallographic structure of the Gli1 / DNA complex were used for Gli1 inhibitors.
Uncontrolled activation of the Hedgehog signalling pathway can lead to numerous types of cancer, including medulloblastoma, basal cell carcinoma, glioma and pancreatic cancer. In order to identify small molecules capable of interfering in the binding of Gli1 (transcription factor and final effector of the pathway) to DNA “, an in-house library composed of more than 1000 natural products was subjected to computational screening (docking) in the DNA binding site of the Gli1 protein (ZF4 and ZF5). This docking made it possible to select six molecules whose activity was evaluated by means of the Gli-dependent transcriptional function assay. The natural isoflavone Glabrescione B (GlaB) has shown efficacy in inhibiting the Hedgehog pathway and tumor growth in vitro and in vivo. These models were used to filter the library in house and select some compounds that were tested in vitro and in vivo. Glabrescione B (GlaB) appears to be a potent specific inhibitor of the Hedgehog signalling pathway, showing anti-tumor effects in vitro and in vivo in models of medulloblastoma and basal cell carcinoma.
- Therapeutic agent for tumors dependent on the Hedgehog signalling pathway;
- Use of Glabrescione B (GlaB) as a sole agent, or in combination with other anticancer agents.
- The molecule is not affected by drug-resistant mutations identified on the SMO receptor in patients treated with SMO antagonists;
- The molecule also works in tumors in which the aberrant activation of Hedgehog, and therefore the hyperactivation of Gli1, occurs independently of SMO;
- Non-toxicity in vivo up to high doses of GlaB;
- Specificity of GlaB for Gli1.