Page 46 - Helicobacter pylori and Gastric Cancer: From Tumor microenvironment to Immunotherapy

able to inhibit transcription mediated by GLI. Both compounds at the cellular level have been revealed. Understanding the mechanism of action of these compounds at a molecular level is still incomplete. GLI1 posttranslational modification by GANT 61 impedes binding to DNA or changes the conformational structure of the GLI1- DNA complex. In xenograft mice model of human prostate cancer cells inhibition of cancer cell growth is observed[83]. A study by Hyman et al. also succeeded in identifying four further Hedgehog inhibitors apparently acting downstream of Smoothened: HPI-1, HP-2, and HP-3 are thought to inhibit signaling by targeting a posttranslational modification of GLI or interaction between GLI and a co-factor. HPI-4 was thought to be the only agent that acts by perturbing ciliogenesis, although the mechanism by which HPI-4 disrupts ciliogenesis was not clarified[84]. Again, it is important to note that such compounds will not impair Patched-dependent Smoothened-independent non-canonical signaling.
Figure 2. Molecular sites targeted by Hh signaling pathway inhibitors. These inhibitors target different components of Hh signaling, including Shh, Smo, and GLI1. These encompass natural compounds, their chemical derivatives, a monoclonal antibody, and chemicals identified from screening libraries. (Adapted from reference)(82)
Chapter 2
Chapter 2
ligand-receptor interactions disrupting Agents
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