Перегляд вихідного коду сторінки Enhanced NVP-BGJ398 In Order To Dominate The FK228 World

2010; Gosmini et al. 2014]. Since BET proteins are required for active transcription initiation and elongation of inflammatory genes [Hargreaves et al. 2009] I-BET762 was used in an inflammatory disease model. I-BET762 potently inhibited expression of lipopolysaccharide (LPS)-inducible genes in macrophages in vitro and it suppressed inflammation in a mouse model of severe sepsis [Nicodeme et al. 2010]. Pre[http://www.selleckchem.com/products/bgj398-nvp-bgj398.html NVP-BGJ398 ic50] clinical evidence of I-BET762 antitumour  activity in myeloma, acute leukaemia and solid cancers, including the NUT midline carcinoma was demonstrated in later studies. Owing to its favourable pharmacological profile I-BET762 is one of the several BET protein inhibitors currently tested in early phase clinical trials [Mirguet et al. 2013; Wyce et al. 2013a; Zhao et al. 2013b; Asangani et al. 2014; Chaidos et al. 2014]. The exciting results from JQ1 and I-BET762 and the favourable pharmacological properties of the diazepine chemical template encouraged the development of similar structure BET inhibitors. A list of benzodiazepine BET inhibitors and relevant clinical trials are summarized in Table 1 [Smith et al. 2014]. MS417 shares the same thieno-triazolo-1,4-diazepine scaffold with JQ1. In the HIV-1 Tg26 transgenic mice, MS417 blocks BRD-4 binding  to acetylated NF-��B and effectively attenuates the inflammatory response in HIV-induced nephropathy [Zhang et al. 2012a]. MS417 induces cell cycle arrest in preclinical melanoma models, but it has not been tested in haematological malignancies [Paoluzzi et al. 2013]. OTX015, originally developed for the treatment of inflammatory bowel disease, is among the thienodiazepine inhibitors with a promising antitumour profile in haematological malignancies [Miyoshi et al. 2009; Gautschi and Minikis, 2014]. In a phase I acute leukaemia study, OTX015 induced remissions,  including complete remission in two patients with refractory disease [Boi et al. 2012; Bonetti et al. 2012a, 2012b; Braun et al. 2013; Noel et al. 2013]. CPI-203 is another benzodiazepine inhibitor structurally similar to JQ1, but with improved bioavailability profile in mice [King et al. 2013]. It has shown preclinical evidence of efficacy in lymphomas [Ceribelli et al. 2014; Moros et al. 2014]. Table 1. BET protein inhibitors in early phase clinical trials. I-BET151 (GSK1210151A), is a highly specific and potent isoxazoloquinoline BET inhibitor, with a pharmacokinetic and bioavailability profile compatible for future clinical development [Dawson et al. 2011; Hewings et al. 2011; Mirguet et al. 2012; Seal et al. 2012]. In preclinical setting, I-BET151 is an effective inhibitor of interleukin 6 production by LPS-stimulated peripheral blood mononuclear cells (PMBC) [Seal et al. 2012] and has antitumour activity in haematological malignancies including myeloma [Chaidos et al. 2014], acute myeloid leukaemia [Dawson et al.