Hedgehog Signaling

The hedgehog (Hh) signaling pathway plays a crucial role in numerous processes of vertebrates and invertebrates, such as embryogenesis, cellular development, and epithelial-mesenchymal transition (EMT). In adult organisms, the Hh pathway is usually inactive, but its aberrant activation is involved in tissue homeostasis, damage repair, and certain diseases, especially cancer. Aberrant activation of the Hh pathway is an important driver of the occurrence and development of basal cell carcinoma, medulloblastoma, pancreatic cancer, lung cancer, colorectal cancer, and other cancers.

In mammals, there are three Hh ligand homologs: Sonic hedgehog (Shh), which is the most well studied and plays a key role in nervous system, limb, and facial development; Indian hedgehog (Ihh), which is mainly involved in bone development and chondrocyte differentiation; Desert hedgehog (Dhh), which is involved in the development of gonads. Initiation of the Hh signaling pathway is based on ligand processing, which results in the formation of a polypeptide with a dual-lipid-modified N-terminal from the autocatalytically cleaved precursor protein. Signal reception is achieved through receptors on the cell membrane, including the Patched (Ptch) and Smoothened (Smo) transmembrane proteins. In the absence of hedgehog ligands, Ptch inhibits the Smo activity, leading to pathway inhibition. When hedgehog ligands bind to Ptch, the inhibition of Smo is relieved, thereby continuing to activate downstream signaling.

Amerigo Scientific offers a variety of chemical compounds as tools for regulating the Hh signaling pathway, which is used to understand disease mechanisms, develop new treatments, and explore cell biology.

Targeting Smoothened (Smo)

Smo, a G-protein coupled receptor, has two variable ligand-binding sites, namely the seven transmembrane helical domain (TMD) and the extracellular cysteine-rich domain (CRD), which regulate Smo activity. In the absence of Hh ligand stimulation, Ptch inhibits Smo to block the cascade. Smo activation requires two mechanisms: Smo needs to be translocated to primary cilia; Smo located on cilia undergoes carboxy-terminal phosphorylation.

Several therapies based on the mechanism of inhibition of Smo have been approved for the treatment of basal cell carcinomas and medulloblastoma driven by mutations in the Hh pathway. By inhibiting the Hh pathway, the self-renewal ability of cancer stem cells can be impaired, making them more sensitive to treatment.

Targeting Glioma-associated oncogene (GLI)

GLI transcription factors are downstream proteins of the Hh signaling pathway. In mammals, Hh signaling activation elicits a transcriptional response mediated by GLI transcription factors in the nucleus of the recipient cell. GLI proteins consist of an amino-terminal transcriptional repression domain, a zinc-finger DNA-binding domain, and a carboxy-terminal transcriptional activation domain. When transcription is not activated, GLI is proteolyzed into a repressor form with a truncated carboxy-terminal activation domain, which inhibits transcription of target genes.

Inhibitors targeting GLI transcription proteins can block its binding to downstream genes and exert an inhibitory effect on Hh signaling pathway. It has been shown that inhibitors targeting GLI are effective against both primary and secondary resistance induced by Smo inhibitors.