Sonidegib, Free Base

Soluble in DMSO. Sonidegib, also known as NPV-LDE-225 and LDE-225, is a potent and selective smoothened (Smo) antagonist. It inhibited the activation of hedgehog signaling, stimulated with 1 nM and 25 nM Ag1.5, with IC50 values of 0.6 and 8 nM, respectively. It inhibited Smo binding with IC50 values of 1.3 nM for mouse Smo and 2.5 nM for human Smo. Sonidegib demonstrated in vivo antitumor activity in subcutaneous and orthotopic Ptch+/-p53-/- medulloblastoma allograft models. Pan S., et al. 'Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist.' ACS Med. Chem. Lett. 1: 130-134 (2010). This research compound is the free base form of sonidegib. We also offer the diphosphate salt form, please see Sonidegib, Diphosphate Salt, Cat. No. [S-4699] Treatment with sonidegib inhibited the Hedgehog-GLI pathway, induced G1 cell cycle arrest, and resulted in decreased viability and induction of apoptosis in human melanoma cell lines in vitro. It demonstrated antitumor activity against human melanoma and reduced GLI1 expression in vivo. Jalili A., et al. 'NVP-LDE225, a potent and selective SMOOTHENED antagonist reduces melanoma growth in vitro and in vivo.' PLoS One 8: e69064 (2013). Addition of the PI3K inhibitor NVP-BKM120 or the dual PI3K-mTOR (mammalian target of rapamycin) inhibitor NVP-BEZ235 to the initial treatment of medulloblastoma with sonidegib markedly delayed the development of resistance to sonidegib in mice. Buonamici S., et al. 'Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma.' Sci. Transl. Med. 2: 51ra70 (2010). Sonidegib inhibited epithelial-mesenchymal transition and human prostate cancer stem cell growth. Nanta R., et al. 'NVP-LDE-225 (Erismodegib) inhibits epithelial-mesenchymal transition and human prostate cancer stem cell growth in NOD/SCID IL2Rgamma null mice by regulating Bmi-1 and microRNA-128.' Oncogenesis 2: e42 (2013). Sonidegib inhibited melanoma cell growth in vitro and in vivo. O'Reilly K.E., et al. 'Hedgehog pathway blockade inhibits melanoma cell growth in vitro and in vivo.' Pharmaceuticals (Basel) 6: 1429-1450 (2013).