Semisynthetic Cyclopamine Analogues as Potent and Orally Bioavailable Hedgehog Pathway Antagonists

Tremblay, Martin; Nevalainen, Marta; Nair, Somarajan; Porter, James R.; Castro, Alfredo; Behnke, Mark L.; Yu, Lin-Chen; Hagel, Margit; White, Kerry; Faia, Kerrie; Grenier, Louis; Campbell, Matthew; Cushing, Jill; Woodward, Caroline; Hoyt, Jennifer; Foley, Michael A.; Read, Margaret; Sydor, Jens; Tong, Jeffrey K.; Palombella, Vito J.; McGovern, Karen; Adams, Julian

doi:10.1021/jm8008508

Cited by 98 publications

(70 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Due to their potent biological activities, steroidal alkaloids have been investigated for their pharmacokinetic and pharmacodynamic characteristics (30)(31)(32)(33). However, up to now, few studies evaluated the pharmacokinetic profile of veratramine and explored its potential gender-associated pharmacokinetics.…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

Gender-Dependent Pharmacokinetics of Veratramine in Rats: In Vivo and In Vitro Evidence

Lyu

Zhang

Zhou

et al. 2016

AAPS J

View full text Add to dashboard Cite

ABSTRACT. Veratramine, a major alkaloid from Veratrum nigrum L., has distinct anti-tumor and antihypertension effects. Our previous study indicated that veratramine had severe toxicity toward male rats. In order to elucidate the underling mechanism, in vivo pharmacokinetic experiments and in vitro mechanistic studies have been conducted. Veratramine was administrated to male and female rats intravenously via the jugular vein at a dose of 50 μg/kg or orally via gavage at 20 mg/kg. As a result, significant pharmacokinetic differences were observed between male and female rats after oral administration with much lower concentrations of veratramine and 7-hydroxyl-veratramine and higher concentrations of veratramine-3-O-sulfate found in the plasma and urine of female rats. The absolute bioavailability of veratramine was 0.9% in female rats and 22.5% in male rats. Further experiments of veratramine on Caco-2 cell monolayer model and in vitro incubation with GI content or rat intestinal subcellular fractions demonstrated that its efficient passive diffusion mediated absorption with minimal intestinal metabolism, suggesting no gender-related difference during its absorption process. When veratramine was incubated with male or female rat liver microsomes/cytosols, significant malepredominant formation of 7-hydroxyl-veratramine and female-predominant formation of veratramine-3-O-sulfate were observed. In conclusion, the significant gender-dependent hepatic metabolism of veratramine could be the major contributor to its gender-dependent pharmacokinetics.

show abstract

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

Gender-Dependent Pharmacokinetics of Veratramine in Rats: In Vivo and In Vitro Evidence

Lyu

Zhang

Zhou

et al. 2016

AAPS J

View full text Add to dashboard Cite

show abstract

“…A widely studied Hh antagonist is cyclopamine, a natural product derived from corn lily (15). Further, a number of cyclopamine derivatives have been described that offer improved pharmacological and inhibitory properties (16).…”

mentioning

confidence: 99%

Selective translocation of intracellular Smoothened to the primary cilium in response to Hedgehog pathway modulation

Wang

Zhou

Walsh

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

179

170

View full text Add to dashboard Cite

“…This was achieved in nature by cyclopamine, a natural product isolated from corn lilies, responsible for inducing cyclopia in newborn sheep, and discovered to be a SMO inhibitor (37). However, the relatively poor oral solubility and specificity of cyclopamine, with consequent off-target effects (38), precluded its use in humans. High-throughput in vitro screens led to the discovery of a large number of other synthetic SMO antagonists, including the now FDA-approved therapeutic vismodegib (Table 1).…”

Section: Development Of Hh Pathway Inhibitorsmentioning

confidence: 99%

Efficacy of Hedgehog Pathway Inhibitors in Basal Cell Carcinoma

Basset-Séguin

Sharpe

Sauvage

2015

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Basal cell carcinoma (BCC) is the most commonly diagnosed cancer. While most BCCs are amenable to surgery, some tumors can reach a more advanced stage or metastasize, and become ineligible for surgical resection or radiotherapy. Abnormal activation of the Hedgehog (Hh) pathway is a key driver in BCC pathophysiology. Consequently, inhibitors of the Hh pathway have been developed. Molecules that inhibit the receptor protein Smoothened (SMO) are the most advanced in clinical development. Vismodegib is the first-in-class SMO inhibitor and has been approved in a number of countries for the treatment of metastatic or locally advanced BCC. Several molecules have demonstrated antitumoral activity, but treatment may be limited in duration by a number of side effects, and it is not yet established whether these agents are truly curative or whether continued treatment will be required. Resistance to SMO inhibition has been reported in the clinic for which incidence and mechanisms must be elucidated to inform future therapeutic strategies. Intermittent dosing regimens to improve tolerability, as well as neoadjuvant use of Hh pathway inhibitors, are currently under investigation. Here, we review the most recent outcomes obtained with Hh inhibitors under clinical investigation in BCC.

show abstract

Semisynthetic Cyclopamine Analogues as Potent and Orally Bioavailable Hedgehog Pathway Antagonists

Cited by 98 publications

References 35 publications

Gender-Dependent Pharmacokinetics of Veratramine in Rats: In Vivo and In Vitro Evidence

Gender-Dependent Pharmacokinetics of Veratramine in Rats: In Vivo and In Vitro Evidence

Selective translocation of intracellular Smoothened to the primary cilium in response to Hedgehog pathway modulation

Efficacy of Hedgehog Pathway Inhibitors in Basal Cell Carcinoma

Contact Info

Product

Resources

About