@article {10843, title = {Repositioning of Tak-475 In Mevalonate Kinase Disease: Translating Theory Into Practice.}, journal = {Curr Med Chem}, volume = {25}, year = {2018}, month = {2018}, pages = {2783-2796}, abstract = {

BACKGROUND: Mevalonate Kinase Deficiency (MKD, OMIM $\#$610377) is a rare autosomal recessive metabolic and inflammatory disease. In MKD, defective function of the enzyme mevalonate kinase, due to a mutation in the MVK gene, leads to the shortage of mevalonate- derived intermediates, which results in unbalanced prenylation of proteins and altered metabolism of sterols. These defects lead to a complex multisystem inflammatory and metabolic syndrome.

OBJECTIVE: Although biologic therapies aimed at blocking the inflammatory cytokine interleukin- 1 can significantly reduce inflammation, they cannot completely control the clinical symptoms that affect the nervous system. For this reason, MKD can still be considered an orphan drug disease. The availability of MKD models reproducing the MKD-systematic inflammation, is crucial to improve the knowledge on its pathogenesis, which is still unknown. New therapies are also required in order to improve pateints{\textquoteright} conditions and their quality of life.

METHODS: MKD-cellular models can be obtained by biochemical inhibition of mevalonatederived isoprenoids. Of note, these cells present an exaggerated response to inflammatory stimuli that can be reduced by treatment with zaragozic acid, an inhibitor of squalene synthase, thus increasing the availability of isoprenoids intermediates upstream the enzymatic block.

RESULTS: A similar action might be obtained by lapaquistat acetate (TAK-475, Takeda), a drug that underwent extensive clinical trials as a cholesterol lowering agent 10 years ago, with a good safety profile.

CONCLUSIONS: Here we describe the preclinical evidence supporting the possible repositioning of TAK-475 from its originally intended use to the treatment of MKD and discuss its potential to modulate the mevalonate pathway in inflammatory diseases.

}, keywords = {Acyl Coenzyme A, Cholesterol, Drug Repositioning, Farnesyl-Diphosphate Farnesyltransferase, Humans, Hypercholesterolemia, Mevalonate Kinase Deficiency, Oxazepines, Phosphotransferases (Alcohol Group Acceptor), Piperidines}, issn = {1875-533X}, doi = {10.2174/0929867324666170911161417}, author = {Marcuzzi, Annalisa and Loganes, Claudia and Celeghini, Claudio and Kleiner, Giulio} } @article {1726, title = {Recent advances in the therapeutic perspectives of Nutlin-3.}, journal = {Curr Pharm Des}, volume = {17}, year = {2011}, month = {2011}, pages = {569-77}, abstract = {

Nutlin-3 is a small molecule inhibitor of the MDM2/p53 interaction, which leads to the non-genotoxic p53 stabilization, activation of cell cycle arrest and apoptosis pathways. A series of recent studies have strengthened the concept that selective, non-genotoxic p53 activation by Nutlin-3 might represent an alternative to the current cytotoxic chemotherapy, in particular for pediatric tumors and for hematological malignancies, which retain a high percentage of p53(wild-type) status at diagnosis. Like most other drugs employed in cancer therapy, it will be unlikely that Nutlin-3 will be used as a monotherapy. In this respect, Nutlin-3 shows a synergistic cytotoxic effect when used in combination with innovative drugs, such as TRAIL or bortozemib. Although Nutlin-3 is currently in phase I clinical trial for the treatment of retinoblastoma, its effects on normal tissues and cell types remain largely to be determined and will require further investigation in the future years.

}, keywords = {Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Drug Synergism, Genes, p53, Humans, Imidazoles, Neoplasms, Piperazines, Proto-Oncogene Proteins c-mdm2, Tumor Suppressor Protein p53}, issn = {1873-4286}, author = {Secchiero, Paola and Bosco, Raffaella and Celeghini, Claudio and Zauli, Giorgio} }