- Protease inhibitors (by machine translation)
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The invention relates to a Grp94 specific Hsp - 90 inhibitor, a protease inhibitor of the preparation method, to solve the existing problems on the preparation method of the blank defect, comprising the following processing steps: in the three flasks, is put into the water-free of dimethyl formamide, under the protection of nitrogen, adding 3, 5 - dichloro dithiol, completely dissolved after stirring, then slowly adding sodium hydride, stirring at room temperature the reaction 1 hours; then and then adding 8 - bromo - 9 - (3 - isopropylamino) propyl adenine, after adding gradually raising the temperature to 150 degrees, reflux reaction for 6 hours; after the reaction is complete cooling to room temperature, the reaction liquid is slowly added to the water, quenching the unreacted sodium hydride, methylene chloride/methanol mixed solution extraction, the organic phase is used for the saturated salt water and saturated ammonium chloride solution washing several times, and then after the saturated sodium bicarbonate multi-time extraction, for water-free magnesium sulfate drying, steaming and, for column chromatography column purification. (by machine translation)
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- Combining a set of gp96 protein the ability of the compound and its the application of anti-breast cancer
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The invention discloses compounds with capability of combining a protein gp96 and application of the compounds to resistance to breast cancer. The compounds are shown in the following (a) or (b): (a) a compound A3 shown in a formula (III), a compound A2 s
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- Structure-activity relationship in a purine-scaffold compound series with selectivity for the endoplasmic reticulum Hsp90 paralog Grp94
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Grp94 is involved in the regulation of a restricted number of proteins and represents a potential target in a host of diseases, including cancer, septic shock, autoimmune diseases, chronic inflammatory conditions, diabetes, coronary thrombosis, and stroke. We have recently identified a novel allosteric pocket located in the Grp94 N-terminal binding site that can be used to design ligands with a 2-log selectivity over the other Hsp90 paralogs. Here we perform extensive SAR investigations in this ligand series and rationalize the affinity and paralog selectivity of choice derivatives by molecular modeling. We then use this to design 18c, a derivative with good potency for Grp94 (IC50 = 0.22 μM) and selectivity over other paralogs (>100- and 33-fold for Hsp90α/β and Trap-1, respectively). The paralog selectivity and target-mediated activity of 18c was confirmed in cells through several functional readouts. Compound 18c was also inert when tested against a large panel of kinases. We show that 18c has biological activity in several cellular models of inflammation and cancer and also present here for the first time the in vivo profile of a Grp94 inhibitor.
- Patel, Hardik J.,Patel, Pallav D.,Ochiana, Stefan O.,Yan, Pengrong,Sun, Weilin,Patel, Maulik R.,Shah, Smit K.,Tramentozzi, Elisa,Brooks, James,Bolaender, Alexander,Shrestha, Liza,Stephani, Ralph,Finotti, Paola,Leifer, Cynthia,Li, Zihai,Gewirth, Daniel T.,Taldone, Tony,Chiosis, Gabriela
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p. 3922 - 3943
(2015/05/27)
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- SELECTIVE GRP94 INHIBITORS AND USES THEREOF
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The disclosure relates to novel selective Grp94 inhibitors, compositions comprising an effective amount of such compounds, and methods to treat or prevent a condition, such as cancer, comprising administering to an animal in need thereof an effective amount of such compounds.
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Paragraph 0358; 0361-0362
(2015/02/25)
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