TAK-475 (
lapaquistat acetate) and its active metabolite-I (TAK-475 M-I) inhibit
squalene synthase, which catalyzes the conversion of
farnesyl diphosphate (FPP) to
squalene. FPP is a substrate for synthesis of other
mevalonate-derived
isoprenoids (MDIs) such as
farnesol (FOH), geranlygeranyl
diphosphate (GGPP), and
geranylgeraniol. In patients with MKD, a rare autosomal recessive disorder, defective activity of
mevalonate kinase leads to a shortage of MDIs. MDIs especially GGPP are required for prenylation of
proteins, which is a posttranslation modification necessary for proper functioning of
proteins like small
guanosine triphosphatases. Malfunction of prenylation of
proteins results in upregulation of the inflammatory cascade, leading to increased production of proinflammatory
cytokines like interleukin-1β (IL-1β), eventually leading to episodic febrile attacks. In vitro,
TAK-475 M-I incubation in a concentration dependent manner increased levels of FPP, GGPP, and FOH in human monocytic THP-1 cells. In subsequent experiments, THP-1 cells or human peripheral blood mononuclear cells (PBMCs) were incubated with
simvastatin, which inhibits hydroxymethylglutaryl-
coenzyme A reductase and thereby decreases levels of the precursors of MDIs, leading to the depletion of MDIs as expected in MKD patients. Increased levels of GGPP and FPP attenuated
lipopolysaccharide (LPS)-induced IL-1β production in THP-1 cells and human PBMCs in
statin-treated conditions. The MDIs also significantly reduced the damaged cell ratio in this active MKD-like condition. Moreover,
TAK-475 M-I directly inhibited LPS-induced IL-1β production from
statin-treated THP-1 cells. These results show anti-inflammatory and cytoprotective effects of MDIs via
TAK-475 M-I treatment in
statin-treated immune cells, suggesting that possible
therapeutic effects of
TAK-475 treatment in MKD patients.