HhAntag

IC50: from ~2 μM to >30 μM

HhAntag is a Hedgehog signaling antagonist. Ligand-dependent activation of the Hedgehog (Hh) signaling pathway has been associated with tumorigenesis in a number of human tissues.

In vitro: HhAntag has been evaluated for its effect on Hh pathway across a large panel of cancer cell lines. HhAntag demonstrated to be around 10-times more potent than cyclopamine at inhibiting the activity of Hh pathway. A range of cellular sensitivities to HhAntag was observed with IC50 values for growth inhibition ranging from ~2 μM to >30 μM. In contrast to previous reports, no tissue specificity of in vitro sensitivity to HhAntag was observed [1].

In vivo: Oral administration of HhAntag to mice with primary human xenografts resulted in significant growth delay in both pancreatic and colon adenocarcinoma models, with average tumour growth inhibitions of 29% and 48%, respectively. Moreover, the HhAntag doses required to inhibit the tumor growth were similar to the doses required to fully inhibit endogenous Hh target genes in tumour stroma or in surrogate normal tissues, indicating that such growth inhibition was a specific consequence of Hh inhibition [1].

Clinical trial: N/A

Reference:
[1] Yauch RL,Gould SE,Scales SJ,Tang T,Tian H,Ahn CP,Marshall D,Fu L,Januario T,Kallop D,Nannini-Pepe M,Kotkow K,Marsters JC,Rubin LL,de Sauvage FJ.  A paracrine requirement for hedgehog signalling in cancer. Nature.2008 Sep 18;455(7211):406-10.

HhAntag, a Hedgehog Signaling Antagonist, Suppresses Chondrogenesis and Modulates Canonical and Non-Canonical BMP Signaling.[Pubmed:26363135]

J Cell Physiol. 2016 May;231(5):1033-44.

Chondrogenesis subtends the development of most skeletal elements and involves mesenchymal cell condensations differentiating into growth plate chondrocytes that proliferate, undergo hypertrophy, and are replaced by bone. In the pediatric disorder Hereditary Multiple Exostoses, however, chondrogenesis occurs also at ectopic sites and causes formation of benign cartilaginous tumors--exostoses--near the growth plates. No treatment is currently available to prevent or reverse exostosis formation. Here, we asked whether chondrogenesis could be stopped by targeting the hedgehog pathway, one of its major regulators. Micromass cultures of limb mesenchymal cells were treated with increasing amounts of the hedgehog inhibitor HhAntag or vehicle. The drug effectively blocked chondrogenesis and did so in a dose-dependent manner as monitored by: alcian blue-positive cartilage nodule formation; gene expression of cartilage marker genes; and reporter activity in Gli1-LacZ cell cultures. HhAntag blocked chondrogenesis even when the cultures were co-treated with bone morphogenetic protein 2 (rhBMP-2), a strong pro-chondrogenic factor. Immunoblots showed that HhAntag action included modulation of canonical (pSmad1/5/8) and non-canonical (pp38) BMP signaling. In cultures co-treated with HhAntag plus rhBMP-2, there was a surprising strong up-regulation of pp38 levels. Implantation of rhBMP-2-coated beads near metacarpal elements in cultured forelimb explants induced formation of ectopic cartilage that however, was counteracted by HhAntag co-treatment. Collectively, our data indicate that HhAntag inhibits not only hedgehog signaling, but also modulates canonical and non-canonical BMP signaling and blocks basal and rhBMP2-stimulated chondrogenesis, thus representing a potentially powerful drug-based strategy to counter ectopic cartilage growth or induce its involution.

HhAntag is a small molecule inhibitor of GLI1-mediated transcription, an essential down-stream element of the Hedgehog (Hh) pathway; antitumor agent.

HhAntag,496794-70-8,Natural Products,Smoothened, buy HhAntag , HhAntag supplier , purchase HhAntag , HhAntag cost , HhAntag manufacturer , order HhAntag , high purity HhAntag