LDE225(NVP-LDE225,Erismodegib)

Molecular Weight (MW)	485.5
Formula	C26H26F3N3O3
CAS No.	956697-53-3 (free base); 1218778-77-8 (phosphate)
Storage	-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)	DMSO: 97 mg/mL (199.8 mM)
Water:<1 mg/mL
Ethanol: 97 mg/mL (199.8 mM)
Solubility (In vivo)	2% DMSO+corn oil: 10 mg/mL
Synonyms	Sonidegib; LDE 225; NVP-LDE225; LDE-225; NVP LDE-225; LDE225; NVP LDE225; Erismodegib; trade name of Odomzo

Molecular Weight (MW)

485.5

Formula

C26H26F3N3O3

CAS No.

956697-53-3 (free base); 1218778-77-8 (phosphate)

Storage

-20℃ for 3 years in powder form

-80℃ for 2 years in solvent

Solubility (In vitro)

DMSO: 97 mg/mL (199.8 mM)

Water:<1 mg/mL

Ethanol: 97 mg/mL (199.8 mM)

Solubility (In vivo)

2% DMSO+corn oil: 10 mg/mL

Synonyms

Sonidegib; LDE 225; NVP-LDE225; LDE-225; NVP LDE-225; LDE225; NVP LDE225; Erismodegib; trade name of Odomzo

In Vitro	In vitro activity: LDE225 (also known as NVP-LDE225, Erismodegib, Sonidegib; trade name of Odomzo) is an orally bioavailable small-molecule antagonist of the Smoothened (Smo) which inhibits the Hedgehog (Hh) signaling with IC50 of 1.3 nM (mouse) and 2.5 nM (human) in cell-free assays, respectively. LDE225 (NVP-LDE225, Erismodegib, Sonidegib) specifically binds to the Hedgehog (Hh)-ligand cell surface receptor Smo, resulting in the suppression of the Hedgehog signaling pathway and thus the inhibition of tumor cell growth in which the Hedgehog pathway is abnormally activated. It is an anticancer drug that received FDA approval in 2015 for the treatment of basal cell carcinoma. Kinase Assay: LDE225 inhibits TM3 luciferized cell line with 0.6 nM and 8 nM, at the presence of 1 nM and 25 nM Hh agonist Ag1.5, respectively. Cell Assay: LDE225 induced apoptosis in a dose-dependent manner. Treatment of prostate CSCs resulted in an increase in the expression of cleaved caspase-3 and PARP. LDE225 inhibited cell viability in primary and secondary spheroids in a dose-dependent manner.
In Vivo	LDE225 is highly bound to mouse, rat, and human plasma proteins (>99%) and moderately bound to dog and monkey plasma proteins (77 and 85%, respectively). LDE225 has high permeability (90.8% in man) in the PAMPA assay. LDE225 shows good oral bioavailability ranging from 69 to 102% in preclinical species when dosed in solution. LDE225 is a weak base with a measured pKa of 4.20 and exhibits relatively poor aqueous solubility. LDE225 demonstrates dose-related antitumor activity. At a dose of 5 mg/kg/day qd, LDE225 significantly inhibits tumor growth, corresponding to a T/C value of 33%. When dosed at 10 and 20 mg/kg/day qd, LDE225 gives rise to 51 and 83% regression, respectively. Gli1 mRNA inhibition correlates with tumor and plasma exposure of LDE225. LDE225 successfully penetrates the blood–brain barrier in tumor-bearing animals and results in tumor growth inhibition after 4 days of treatment. 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.
Animal model	Orthotopic Ptch+/-p53-/- medulloblastoma allograft model in athymic nude mice
Formulation & Dosage	Dissolved in 0.5% sodium carboxymethyl cellulose, and diluted in saline; 40 mg/kg; Oral administration
References	Ann Surg. 2011 Nov;254(5):818-23; ACS Med. Chem. Lett., 2010, 1 (3), 130–134.

In Vitro

In vitro activity: LDE225 (also known as NVP-LDE225, Erismodegib, Sonidegib; trade name of Odomzo) is an orally bioavailable small-molecule antagonist of the Smoothened (Smo) which inhibits the Hedgehog (Hh) signaling with IC50 of 1.3 nM (mouse) and 2.5 nM (human) in cell-free assays, respectively. LDE225 (NVP-LDE225, Erismodegib, Sonidegib) specifically binds to the Hedgehog (Hh)-ligand cell surface receptor Smo, resulting in the suppression of the Hedgehog signaling pathway and thus the inhibition of tumor cell growth in which the Hedgehog pathway is abnormally activated. It is an anticancer drug that received FDA approval in 2015 for the treatment of basal cell carcinoma.

Kinase Assay: LDE225 inhibits TM3 luciferized cell line with 0.6 nM and 8 nM, at the presence of 1 nM and 25 nM Hh agonist Ag1.5, respectively.

Cell Assay: LDE225 induced apoptosis in a dose-dependent manner. Treatment of prostate CSCs resulted in an increase in the expression of cleaved caspase-3 and PARP. LDE225 inhibited cell viability in primary and secondary spheroids in a dose-dependent manner.

In Vivo

LDE225 is highly bound to mouse, rat, and human plasma proteins (>99%) and moderately bound to dog and monkey plasma proteins (77 and 85%, respectively). LDE225 has high permeability (90.8% in man) in the PAMPA assay. LDE225 shows good oral bioavailability ranging from 69 to 102% in preclinical species when dosed in solution. LDE225 is a weak base with a measured pKa of 4.20 and exhibits relatively poor aqueous solubility. LDE225 demonstrates dose-related antitumor activity. At a dose of 5 mg/kg/day qd, LDE225 significantly inhibits tumor growth, corresponding to a T/C value of 33%. When dosed at 10 and 20 mg/kg/day qd, LDE225 gives rise to 51 and 83% regression, respectively. Gli1 mRNA inhibition correlates with tumor and plasma exposure of LDE225. LDE225 successfully penetrates the blood–brain barrier in tumor-bearing animals and results in tumor growth inhibition after 4 days of treatment. 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.

Animal model

Orthotopic Ptch+/-p53-/- medulloblastoma allograft model in athymic nude mice

Formulation & Dosage

Dissolved in 0.5% sodium carboxymethyl cellulose, and diluted in saline; 40 mg/kg; Oral administration

References

Ann Surg. 2011 Nov;254(5):818-23; ACS Med. Chem. Lett., 2010, 1 (3), 130–134.

CAS NO:	956697-53-3
规格:	≥98%

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