Squalene synthase, the first committed enzyme for sterol synthesis, converts farnesyl pyrophosphate to squalene with presqualene pyrophosphate as an intermediate. It was discovered that BM 21.0955 (1-hydroxy-3-(methylpentylamino)-propylidene-1,1-bisphosphon ic acid), in development for the treatment of bone disorders, inhibited rat liver microsomal squalene synthase (K(i) = nmol/l). BM 21.0955 also inhibited sterol biosynthesis from mevalonate (IC50 = 42 nmol/l), and cholesterol biosynthesis in J774 cells (IC50 = mumol/l). Structural modifications on this molecule to make it more lipophilic may result in a new class of cholesterol-lowering agents.
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Article Synopsis
- The study aimed to explore the effects of targeting the mevalonate pathway (MVP) in rhabdomyosarcoma (RMS), a common soft tissue tumor in young individuals.
- In silico analyses showed that higher levels of MVP-related genes correlated with poorer patient survival, while in vitro tests revealed that MVP inhibitors significantly reduced RMS cell growth, migration, and survival.
- In vivo experiments demonstrated the effectiveness of MVP inhibition in RMS xenografts, highlighting the potential of these inhibitors as a therapeutic strategy against RMS.
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