Novel, potent, selective, and metabolically stable stearoyl-CoA desaturase (SCD) inhibitors

Koltun, Dmitry O.; Parkhill, Eric Q.; Vasilevich, Natalya I.; Glushkov, Andrei I.; Zilbershtein, Timur M.; Ivanov, Alexei V.; Cole, Andrew G.; Henderson, Ian; Zautke, Nathan A.; Brunn, Sandra A.; Mollova, Nevena; Leung, Kwan; Chisholm, Jeffrey W.; Zablocki, Jeff

doi:10.1016/j.bmcl.2009.02.019

Cited by 55 publications

(27 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Oleic acid was obtained from NuCheck Prep (Elysian, MN) and [ 14 C] stearic acid from Perkin-Elmer (Courtaboeuf, France). Scd1 inhibitors CVT-11127 and MF-438 were generous gift from Gilead Sciences, Inc. and Merck Frosst, respectively [62], [63].…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Stearoyl-CoA Desaturase 1 Expression Induces CHOP-Dependent Cell Death in Human Cancer Cells

et al. 2010

View full text Add to dashboard Cite

BackgroundCancer cells present a sustained de novo fatty acid synthesis with an increase of saturated and monounsaturated fatty acid (MUFA) production. This change in fatty acid metabolism is associated with overexpression of stearoyl-CoA desaturase 1 (Scd1), which catalyses the transformation of saturated fatty acids into monounsaturated fatty acids (e.g., oleic acid). Several reports demonstrated that inhibition of Scd1 led to the blocking of proliferation and induction of apoptosis in cancer cells. Nevertheless, mechanisms of cell death activation remain to be better understood.Principal FindingsIn this study, we demonstrated that Scd1 extinction by siRNA triggered abolition of de novo MUFA synthesis in cancer and non-cancer cells. Scd1 inhibition-activated cell death was only observed in cancer cells with induction of caspase 3 activity and PARP-cleavage. Exogenous supplementation with oleic acid did not reverse the Scd1 ablation-mediated cell death. In addition, Scd1 depletion induced unfolded protein response (UPR) hallmarks such as Xbp1 mRNA splicing, phosphorylation of eIF2α and increase of CHOP expression. However, the chaperone GRP78 expression, another UPR hallmark, was not affected by Scd1 knockdown in these cancer cells indicating a peculiar UPR activation. Finally, we showed that CHOP induction participated to cell death activation by Scd1 extinction. Indeed, overexpression of dominant negative CHOP construct and extinction of CHOP partially restored viability in Scd1-depleted cancer cells.ConclusionThese results suggest that inhibition of de novo MUFA synthesis by Scd1 extinction could be a promising anti-cancer target by inducing cell death through UPR and CHOP activation.

show abstract

Section: Methodsmentioning

confidence: 99%

Inhibition of Stearoyl-CoA Desaturase 1 Expression Induces CHOP-Dependent Cell Death in Human Cancer Cells

et al. 2010

View full text Add to dashboard Cite

show abstract

“…MUFAs are important for tumorigenesis because they are important constituents of the phospholipid cell membrane and are thought to affect its biomechanical integrity [16]. Inhibition of MUFA synthesis by SCD-1 inhibitors, such as CVT-11127 [17], has been proposed as a strategy for reducing tumor growth by attenuating cell proliferation at the G 1 /S cell cycle phase and initiating apoptosis [18], although concomitant inhibition of ACC in lung cancer cells does not augment the suppression of cell proliferation by SCD-1 inhibition alone [18].…”

Section: Fatty Acid Metabolismmentioning

confidence: 99%

Non-glucose metabolism in cancer cells—is it all in the fat?

Biswas

Lunec

Bartlett

2012

Cancer Metastasis Rev

View full text Add to dashboard Cite

“…One of the most potent pteridinone analogs is 19 (IC 50 5 0.6 nM versus rSCD, IC 50 5 0.05 nM in HepG2 cells) with good liver microsome stability. 64 Compound 20 (CVT-11,563) was discovered by scaffold-hopping from a HTS hit using a quinazolin-4-one core template. It has IC 50 values of 267 nM (rSCD) and 79 nM (HepG2), and reasonable exposure (AUC 5 935 ng?h/mL) and high oral bioavailability (90%).…”

Section: Pteridinones and Related Analogsmentioning

confidence: 99%

Chapter 9. Stearoyl-CoA Desaturase 1 (SCD1) Inhibitors: Bench to Bedside Must Only Go Through Liver

Liu¹

2012

Drug Discovery

View full text Add to dashboard Cite

Novel, potent, selective, and metabolically stable stearoyl-CoA desaturase (SCD) inhibitors

Cited by 55 publications

References 21 publications

Inhibition of Stearoyl-CoA Desaturase 1 Expression Induces CHOP-Dependent Cell Death in Human Cancer Cells

Inhibition of Stearoyl-CoA Desaturase 1 Expression Induces CHOP-Dependent Cell Death in Human Cancer Cells

Non-glucose metabolism in cancer cells—is it all in the fat?

Chapter 9. Stearoyl-CoA Desaturase 1 (SCD1) Inhibitors: Bench to Bedside Must Only Go Through Liver

Contact Info

Product

Resources

About