MRT-83, a Potent Smoothened Antagonist, has Potential to Treat Hh-pathway Related Diseases

The Hedgehog (Hh) signaling pathway participates in developmental processes and multiple physiological responses in adult tissues, including the control of brain functions. Hh pathway activation via an Hh peptide to the 12-pass transmembrane protein Patched (Ptc). However, in the absence of its ligand, repression of the activation of the seven-pass transmembrane protein Smoothened (Smo) is blocked. Besides, Smo is a proposed member of the G-proteincoupled receptor (GPCR) family. A study from Hermine Roudaut discovered and identified a a potent antagonist of Smo, with an IC₅₀ in the nanomolar range.

In vitro, MRT-83 displays full antagonist properties with an IC₅₀ of ~3 nM for inhibiting ShhN (3 nM)-induced proliferation of rat GCPs. In addition, MRT-83 also blocks SAG (0.01 μM)-induced proliferation of GCPs (IC₅₀ ~6 nM). MRT-83 also blocks BC binding to HEK-hSmo cells in a dose-dependent manner with an IC₅₀ of 4.6 nM. Likewise, MRT-83 abrogates BC binding to cells expressing mouse Smo with an IC₅₀ of 14 nM, which is in good correlation with its IC₅₀ in the Shh-light2 and alkaline phosphatase assays.

In vivo, animals treated with ShhN in the presence of MRT-83 keep as healthy as those of the other groups. However, up-regulation of Ptc transcription in the SVZ of these animals is no longer observed in agreement with complete inhibition of ShhN-mediated effects. And it doesn’t differ from vehicle-mediated effects. MRT-83 but not MRT-36 antagonizes the up-regulation of Ptc transcription induced by ShhN in the SVZ of the LV.

Reference:
Roudaut H, et al. Identification and mechanism of action of the acylguanidine MRT-83, a novel potent Smoothened antagonist. Mol Pharmacol. 2011 Mar;79(3):453-60.