Page 45 - Helicobacter pylori and Gastric Cancer: From Tumor microenvironment to Immunotherapy

Hedgehog Signaling pathway inhibitors
The Hedgehog signaling pathway is a significant target in cancer therapy. Various molecules that may inhibit the pathway have been evaluated in both preclinical and clinical studies. These inhibitors include: SMO inhibitors, ligand-receptor inhibitors, Gli targeted inhibitors, and these classes of molecules are adstructed in figure 2.
SMO Inhibitors
Cyclopamine, originally isolated from the flower veratrum californicum that causes birth defects when eaten by pregnant cattle, was the first compound that was used as a Hedgehog inhibitor and it targets SMO. Consequently, GLIs activation is inhibited. In the clinic, it is side effect-prone and exhibits substantial toxicity[79]. Frustratingly, mice studies involving rhabdomyosarcoma and osteosarcoma models, reveal no significant impact on cancer cells metastasis or growth[80, 81]. From mouse model studies, skin ulcerations and scrubby coat were reported as particularly noticeable skin toxicity; halted even studies initiated to ascertain cyclopamine therapeutic dosing[81]. Adverse effects of cyclopamine in conjunction with other limitations such as acid sensitivity and poor solubility have now halted its clinical development as a potential compound for the treatment of cancer and prompted efforts aimed at. Identifying molecules potentially more suited. This led to the development of the acid stable and water-soluble compound vismodegib (GDC- 0449), which was eventually approved by the FDA for the treatment of advanced (Locally), recurrent and metastatic skin cancer. Another semisynthetic novel analogue of cyclopamine (Saridegib (IPI-926) was developed with enhanced potency and metabolically stable[82]. Other inhibitors that impede SMO include LEQ506, PF-0449913, LDE-225 (erismodegib), and BMS-833923. It is important to note that such compounds will not impair Patched-dependent Smoothened- independent non-canonical signaling.
GLI inhibitors
Also in view of resistance development against vismodegib through SMO mutation efforts have been made to target Gli. Two inhibitory compounds (GANT 58. And GANT 56) were identified through cellular screens aimed at identifying compounds
Gastric cancer and Hedgehog signalling
Gastric cancer and the Hedgehog Signalling
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