LDE225 is a potent and selective Hedgehog signaling pathway inhibitor (Smoothened antagonist) reduces melanoma growth in vitro and in vivo. NVP-LDE225 was potent in reducing cell proliferation and inducing tumor growth arrest in vitro and in vivo, respectively.Pharmacologic inhibition of BRAF(V600E) in human melanoma cell lines resulted in decreased expression of GLI1 thus demonstrating interaction of SHH-GLI and MAPK pathways. Inhibition of SHH-GLI pathway by the novel small molecule inhibitor of smoothened NVP-LDE225 was followed by inhibition of cell growth and induction of apoptosis in human melanoma cell lines, interestingly with both BRAF(V600E) and BRAF(Wild Type) status.LDE225 significantly reduces the tumor volume by 95.7% in Rip1-Tag2 mice. LDE225 prolongs survival in Rip1Tag2 mice. LDE225 decreases expression of stromal markers in the LDE225-treated mice.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist.
Pan S, et al. ACS Med Chem Lett. 2010 Mar 16;1(3):130-4. PMID: 24900187.
NVP-LDE225, a potent and selective SMOOTHENED antagonist reduces melanoma growth in vitro and in vivo.
Jalili A, et al. PLoS One. 2013 Jul 30;8(7):e69064. PMID: 23935925.
Hedgehog inhibition with the orally bioavailable Smo antagonist LDE225 represses tumor growth and prolongs survival in a transgenic mouse model of islet cell neoplasms.
Fendrich V, et al. Ann Surg. 2011 Nov;254(5):818-23. PMID: 22042473.
|Related Hedgehog Products|
HPI-4 (Ciliobrevin A) is a hedgehog (Hh) pathway antagonist. It blocks Sonic hedgehog (Shh)-induced Hh pathway activation (IC50 = 7 μM) downstream of Smo.
|Smoothened Agonist (SAG) HCl
Smoothened Agonist (SAG) HCl is a cell-permeable Smoothened (Smo) agonist with EC50 of 3 nM in Shh-LIGHT2 cells.
Jervine is a naturally occuring steroidal alkaloid that causes cyclopia by blocking sonic hedgehog signaling.
GANT61 is an inhibitor for GLI1 as well as GLI2-induced transcription, inhibits hedgehog with IC50 of 5 μM.
PF-5274857 is a novel Smoothened antagonist, inhibits Hedgehog signaling with IC50 and Ki values of 5.8 nM and 4.6 nM, respectively.
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