933190-51-3Relevant articles and documents
Design, synthesis, and biological evaluation of imidazo[1,2-b]pyridazine derivatives as mTOR inhibitors
Mao, Beibei,Gao, Shanyun,Weng, Yiran,Zhang, Liangren,Zhang, Lihe
, p. 135 - 150 (2017)
ATP-competitive mTOR inhibitors have been studied as potential antitumor agents. Based on the structure-activity relationship of known mTOR inhibitors, a series of novel imidazo[1,2-b]pyridazine derivatives were synthesized and characterized. The anti-proliferative activities of these compounds were evaluated by SRB assay against six human cancer cell lines. Imidazo[1,2-b]pyridazine diaryl urea derivatives A15?A24 exhibited significant anti-proliferative activity especially against non-small cell lung cancer A549 and H460 with IC50values ranging from 0.02?μM to 20.7?μM. Among them, compounds A17 and A18 showed mTOR inhibitory activity with IC50of 0.067?μM and 0.062?μM, respectively. A more detailed analysis of compounds A17 and A18 showed that they induced G1-phase cell cycle arrest and suppressed the phosphorylation of AKT and S6 at cellular level. Moreover, obvious anticancer effect of A17 in?vivo was observed in established nude mice A549 xenograft model.
Binding to an Unusual Inactive Kinase Conformation by Highly Selective Inhibitors of Inositol-Requiring Enzyme 1α Kinase-Endoribonuclease
Colombano, Giampiero,Caldwell, John J.,Matthews, Thomas P.,Bhatia, Chitra,Joshi, Amar,McHardy, Tatiana,Mok, Ngai Yi,Newbatt, Yvette,Pickard, Lisa,Strover, Jade,Hedayat, Somaieh,Walton, Michael I.,Myers, Stephanie M.,Jones, Alan M.,Saville, Harry,McAndrew, Craig,Burke, Rosemary,Eccles, Suzanne A.,Davies, Faith E.,Bayliss, Richard,Collins, Ian
, p. 2447 - 2465 (2019/03/17)
A series of imidazo[1,2-b]pyridazin-8-amine kinase inhibitors were discovered to allosterically inhibit the endoribonuclease function of the dual kinase-endoribonuclease inositol-requiring enzyme 1α (IRE1α), a key component of the unfolded protein response in mammalian cells and a potential drug target in multiple human diseases. Inhibitor optimization gave compounds with high kinome selectivity that prevented endoplasmic reticulum stress-induced IRE1α oligomerization and phosphorylation, and inhibited endoribonuclease activity in human cells. X-ray crystallography showed the inhibitors to bind to a previously unreported and unusually disordered conformation of the IRE1α kinase domain that would be incompatible with back-to-back dimerization of the IRE1α protein and activation of the endoribonuclease function. These findings increase the repertoire of known IRE1α protein conformations and can guide the discovery of highly selective ligands for the IRE1α kinase site that allosterically inhibit the endoribonuclease.
Synthesis method of 6-cholro-8-bromoimidazole[1,2-b]pyridazine
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Paragraph 0027, (2017/01/02)
The invention relates to a synthesis method of 6-chloro-8-bromoimidazole[1,2-b]pyridazine. 3-amino-6-chloropyridazine, liquid bromine, and a chloroacetaldehyde water solution are taken as the raw materials, the ratio of amount of substance of 3-amino-6-chloropyridazine to liquid bromine is 1:1.0-4.5, the ratio of amount of substance of 3-amino-6-chloropyridazine to the chloroacetaldehyde water solution (40%) is 5:1.0-1:3.2; in a proper solvent, in the presence of alkali, raw materials carry out continuous reactions at a temperature of 50 to 100 DEG C to generate a coarse product of 6-cholro-8-bromoimidazole[1,2-b]pyridazine, and then the coarse product is purified to obtain purified product of 6-cholro-8-bromoimidazole[1,2-b]pyridazine. The provided synthesis method has the advantages that the raw materials are easily available, the prices are reasonable, at the same time, no heavy metal or corrosive gas is used in the preparation reactions, the reactions are mild, there is no special requirement on reaction equipment, the product can be produced by common corrosion resistant equipment, and the reaction conditions are moderate.
