IC50: 1.3 and 2.5 nM for Mouse and Human Smo

LDE225 is a potent and selective smoothened antagonist. Smoothened (Smo) is a 7-pass transmembrane protein functioning as the key activator of the hedgehog (Hh) signaling pathway. Hh signaling is tightly controlled during cellular differentiation, proliferation, and embryonic morphogenesis. Hh signaling has been linked to tumorigenesis in several cancers.

In vitro: LDE225 was found to selectively bind to the Hedgehog (Hh)-ligand cell surface receptor Smo, which might result in the suppression of the Hh signaling pathway and, therefore, the inhibition of tumor cells in which this pathway was abnormally activated [1].

In vivo: In the subcutaneous medulloblastoma allograft mouse model, LDE225 demonstrated dose-related antitumor activity after 10 days of oral administration of a suspension. At a dose of 5 mg/kg/ day qd, LDE225 inhibited tumor growth significantly, corresponding to a T/C value of 33%. When dosed at 10 and 20 mg/kg/day qd, LDE225 afforded 51 and 83% regression, respectively [1].

Clinical trial: In a phase I study, it was found that LDE225 had an acceptable safety profile in patients with advanced solid tumors and exhibited antitumor activity in advanced BCC and relapsed medulloblastoma, both of which were associated with hedgehog pathway strongly, as shown by gene expression [2].

References:
[1] Shifeng Pan,Xu Wu,Jiqing Jiang et al.? Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist. ACS Med Chem Lett. 2010 Jun 10; 1(3): 130–134.
[2] Rodon J,Tawbi HA,Thomas AL,Stoller RG,Turtschi CP,Baselga J,Sarantopoulos J,Mahalingam D,Shou Y,Moles MA,Yang L,Granvil C,Hurh E,Rose KL,Amakye DD,Dummer R,Mita AC.? A phase I, multicenter, open-label, first-in-human, dose-escalation study of the oral smoothened inhibitor Sonidegib (LDE225) in patients with advanced solid tumors. Clin Cancer Res.2014 Apr 1;20(7):1900-9.