LY2940680 binds to the Smoothened (Smo) receptor and potently inhibits Hedgehog (Hh) signaling.
Smoothened (Smo) is a GPCR-like receptor that, with Patched, mediates hedgehog (Hh) signaling to regulate gene expression through the Gli transcription factors. LY2940680 is an antitumor agent that binds to the human Smo receptor and inhibits Sonic Hh-induced Gli1 expression (IC50 = ~2.4 nM in vitro). The potential anticancer activity of LY2940680 is currently under clinical investigation.[Cayman Chemical]
ly2940680 is a selective inhibitor of smo receptor and thus inhibits hh signaling pathway [1].smoothened(smo) receptor is a member of class f g protein-coupled receptors, which plays an important role in the main transducer of the hedgehog (hh) signaling pathway that implicated in a wide range of developmental and adult processes [2].ly2940680 is a potent smo receptor inhibitor that binds mostly to extracelluar loops and has a different functioning site with the reported smo receptor inhibitor sant-1 which binds to 7tm [2]. when tested with cell lines containing a mutation in the gene encoding smoothened that researchers had previously observed in patient with cancer who developed resistance to vismodegib, ly2940680 inhibited cell proliferation [3].many studies have shown that hh signaling pathway plays a pivotal role in cscs and hh inhibition caused many aspects of transformation attributed to cscs. in patients with basal cell carcinoma and medulloblastoma, ly2940680 showed good efficacy as a monotherapy [1].
Example 14 - Procedure for the synthesis of N-fluoro-N-methyl-N-[1-[4-(1-methyl-1H-pyrazol-5-yl)-1-phthalazinyl]-4-piperidinyl]-2-(trifluoromethyl)benzamide: N-methyl-1-[4-(1-methyl-1H-pyrazol-5-yl)phthalazin-1-yl]piperidin-4-amine (2.8 g, 8.68 mmol) and triethylamine ( 3.36 mL, 26.1 mmol) were dissolved in dichloromethane (30 mL) and 4-fluoro-2-(trifluoromethyl)benzoyl chloride (2.14 mL, 10.42 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure. The resulting residue was purified by fast silica gel chromatography with an eluent ratio of hexane:ethyl acetate:methanol solution of 2M NH3 = 20:5:1 to give the target product, free base, as a yellow foam (3.83 g, 86% yield). Mass spectral analysis showed ES/MS m/z 513.0 ([M+H]+).
[1]. justilien, v. and a.p. fields, molecular pathways: novel approaches for improved therapeutic targeting of hedgehog signaling in cancer stem cells. clin cancer res, 2015. 21(3): p. 505-13.
[2]. hoch, l., et al., mrt-92 inhibits hedgehog signaling by blocking overlapping binding sites in the transmembrane domain of the smoothened receptor. faseb j, 2015. 29(5): p. 1817-29.
[3]. redmond, e.m., et al., investigational notch and hedgehog inhibitors--therapies for cardiovascular disease. expert opin investig drugs, 2011. 20(12): p. 1649-64.
![4-Piperidinamine, N-methyl-1-[4-(1-methyl-1H-pyrazol-5-yl)-1-phthalazinyl]-](/CAS/20210111/GIF/1258861-50-5.gif)
