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Chemical Structure| 79-63-0 Chemical Structure| 79-63-0
Chemical Structure| 79-63-0

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Lanosterol is a key triterpenoid intermediate in the biosynthesis of Cholesterol.

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T. Ishida, Chiaki ; Kubota, Casie S ; Carlyle, Evan ; Tsukamoto, Takashi ; Espenshade, Peter J ;

Abstract: Sterol regulatory element-binding protein (SREBP) transcription factors are central regulators of homeostasis and are essential for metabolic reprogramming that supports tumor growth in multiple cancers. SREBP pathway inhibitors have been identified, but bioavailable compounds are lacking. To address this need, we designed a novel approach for screening a collection of 4,474 FDA-approved drugs. SREBPs are conditionally essential and required under low conditions. Leveraging this property, we screened for drugs that inhibited pancreatic cancer cell growth in lipid-poor, but not lipid-rich, medium. The primary screen identified 83 drugs that inhibited cell growth in a lipid-dependent manner. Secondary assays examining SREBP target gene expression, SREBP proteolytic cleavage, and effects on human breast cancer cells identified 13 FDA-approved drugs that inhibit SREBP pathway activation. Taken together, we demonstrated that our screening approach can identify SREBP inhibitors from a small library of compounds. This high-throughput screening platform enables screening of large compound collections to discover novel small molecule SREBP inhibitors.

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McCarty, Kevin D. ; Sullivan, Molly E. ; Tateishi, Yasuhiro ; Hargrove, Tatiana Y. ; Lepesheva, Galina I. ; Guengerich, F. Peter

Abstract: Cytochrome P 450 (P 450, CYP) family 51 enzymes catalyze the 14α-demethylation of sterols, leading to critical products used for membranes and the production of steroids, as well as signaling mols. In mammals, P 450 51 catalyzes the 3-step, 6-electron oxidation of lanosterol to form (4β,5α)-4,4-dimethyl-cholestra-8,14,24-trien-3-ol (FF-MAS). P 450 51A1 can also use 24,25-dihydrolanosterol (a natural substrate in the Kandutsch-Russell cholesterol pathway). 24,25-Dihydrolanosterol and the corresponding P 450 51A1 reaction intermediates, the 14α-alc. and -aldehyde derivatives of dihydrolanosterol, were synthesized to study the kinetic processivity of the overall 14α-demethylation reaction of human P 450 51A1. A combination of steady-state kinetic parameters, steady-state binding constants, dissociation rates of P 450-sterol complexes, and kinetic modeling of the time course of oxidation of a P 450-dihydrolanosterol complex showed that the overall reaction is highly processive, with koff rates of P 450 51A1-dihydrolanosterol and the 14α-alc. and 14α-aldehyde complexes being 1 to 2 orders of magnitude less than the forward rates of competing oxidations epi-Dihydrolanosterol (the 3α-hydroxy analog) was as efficient as the common 3β-hydroxy isomer in the binding and formation of dihydro FF-MAS. The common lanosterol contaminant dihydroagnosterol was found to be a substrate of human P 450 51A1, with roughly one-half the activity of dihydrolanosterol. Steady-state experiments with 14α-Me deuterated dihydrolanosterol showed no kinetic isotope effect, indicating that C-14α C-H bond breaking is not rate-limiting in any of the individual steps. The high processivity of this reaction generates higher efficiency and also renders the reaction less sensitive to inhibitors.

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Product Details of Lanosterol

CAS No. :79-63-0
Formula : C30H50O
M.W : 426.72
SMILES Code : CC1(C)C(O)CC[C@]2(C)C3=C([C@@]4(CC[C@@H]([C@]4(CC3)C)[C@H](C)CCC=C(C)C)C)CCC12
MDL No. :MFCD00021108
InChI Key :CAHGCLMLTWQZNJ-BQNIITSRSA-N
Pubchem ID :246983

Safety of Lanosterol

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338
 

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