NVP-LDE225

Absorption

Sonidegib is rapidly absorbed in the fasted state with peak concentrations occurring 2-4 hours after administration. (2) However, the total absorption of Sonidegib is low (roughly 6-7%). (1)

Toxicity

Adverse events occurred more frequently with higher doses, 800 mg once daily when compared to a lower dose of 200 mg once daily. In the 200 mg group, frequent adverse events (occurring in ≥2% of patients) included: elevated creatine phosphokinase (6%), increased lipase (5%), muscle spasms (3%), asthenia (3%), and hypertension (3%). In the 800 mg group, frequent adverse events included: elevated creatine phosphokinase (13%), increased lipase (5%), weight loss (5%), muscle spasms (5%), decreased appetite (4%), rhabdomyolysis (3%), nausea (3%), hypertension (3%), increased alanine aminotransferase (3%), increased aspartate aminotransferase (3%), fatigue (2%), syncope (2%), anaemia (2%), dehydration (2%), hyperkalaemia (2%) and myalgia (2%). Rhabdomyolysis cases reported by investigators were not confirmed by the adjudication committee on muscle toxicity or the independent safety review. (2)

The Uses of NVP-LDE225

A potent, selective and orally bioavailable Smoothened (SMO) antagonist; it inhibits hedgehog (Hh) signaling pathway via antagonism of the Smoothened receptor (SMO). Antineoplastic.

The Uses of NVP-LDE225

A potent, selective and orally bioavailable Smoothened (SMO) antagonist; it inhibits hedgehog (Hh) signaling pathway via antagonism of the Smoothened receptor (SMO). Antineoplastic. Potent Hedgehog inhibitor.

Background

Sonidegib is a Hedgehog signaling pathway inhibitor (via smoothened antagonism) developed as an anticancer agent by Novartis. It was FDA approved in 2015 for the treatment of basal cell carcinoma.

Indications

Sonidegib is approved for use in the US and EU for treatment of adults with locally advanced basal cell carcinoma (BCC) that has recurred post surgery or radiation therapy. It is also approved for adult patients with BCC who are not eligible for surgery or radiation therapy. (2)

What are the applications of Application

Erismodegib is a selective Smo (Smoothened) antagonist

Definition

ChEBI: A member of the classo of biphenyls that is the amide obtained by formal condensation of the carboxy group of 2-methyl-4'-(trifluoromethoxy)[1,1'-biphenyl]-3-carboxylic acid with the amino group of 6-(2,6-dimethylmorpholin-4-yl)pyridin-3-amine. Used (as it phosphate salt) for treatment of locally advanced basal cell carcinoma.

Biological Activity

lde225 is a potent and selective inhibitor of smoothened with ic50 values of 1.3nm in mouse and 2.5nm in human, respectively [1].lde225 is screened out from a high-throughput cell-based screen of in-house diversity combinatorial libraries and is developed to be an antagonist of smo. smo is an activator of the hedgehog(hh) signaling pathway and aberrant activation links to tumorigenesis in several cancers. the antitumor efficacy of lde225 has been evaluated in vivo. in the subcutaneous ptch+/-p53-/- medulloblastoma allograft mouse model, lde225 can significantly inhibit tumor growth at a dose of 5mg/kg/day. and in an orthotopic ptch+/-p53-/- medulloblastoma allograft model, lde225 is suggested to penetrate the blood-brain barrier in tumor-bearing animals and cause the tumor growth inhibition after 4 days of treatment. additionally, the preclinical safety assays show that lde225 has no genotoxicity and has good selectivity [1].

Pharmacokinetics

Sonidegib has been shown to inhibit a transmembrane protein called SMO which plays a role in Hh signal transduction. This has resulted in inhibition of Hh signaling as well as antitumour activity in various animal models. In a transgenic mouse model of islet cell neoplasms, tumour volume was reduce by 95% in mice treated with sonidegib when compared with untreated mice. (2)

Metabolism

Sonidegib is primarily metabolized via oxidation and amide hydrolysis. (1) The enzyme responsible for the majority of metabolism is the cytochrome P450 (CYP) 3A4 enzyme. (2)

storage

Store at -20°C

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, 1: 130–134.