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    • 28. 发明授权
    • Redox-stable, non-phosphorylated cyclic peptide inhibitors of SH2 domain binding to target protein, conjugates thereof, compositions and methods of synthesis and use
    • 与靶蛋白结合的SH2结构域的氧化还原稳定的非磷酸化环肽抑制剂,其结合物,组合物和合成和使用方法
    • US06951915B2
    • 2005-10-04
    • US09998350
    • 2001-11-30
    • Peter P. RollerYa-Qiu LongFeng-Di T. LungC. Richter KingDajun Yang
    • Peter P. RollerYa-Qiu LongFeng-Di T. LungC. Richter KingDajun Yang
    • A61K38/00C07K7/06C07K7/56C07K7/00A61K31/00C07K7/50
    • C07K7/06A61K38/00C07K7/56
    • A compound of formula: in which L is sulfur, sulfoxide, oxygen or methylene, and a compound of formula: in which (i) aa1 is Adi and aa4 is Glu or (ii) each of aa1 and aa4 is Adi, L is sulfur, sulfoxide, oxygen or methylene, which compounds (and their conjugates) bind to an SH2 domain in a protein comprising an SH2 domain, are non-phosphorylated, are redox-stable in vivo, are characterized by an IC50 in vivo of less than about 4.0 μM with respect to the SH2 domain in Grb2, and, upon binding to the SH2 domain of Grb2, have a turn conformation. A conjugate comprising a compound as described above and a carrier agent, a composition comprising (i) a compound or a conjugate as described above and (ii) a carrier, a method of inhibiting binding of an SH2 domain in a protein comprising an SH2 domain to a target protein in an animal, wherein the SH2 domain is contacted with a target protein-binding inhibiting effective amount of a compound or a conjugate as described above, and a method of synthesizing such conjugates.
    • 下式的化合物:其中L是硫,亚砜,氧或亚甲基,以及下式的化合物:其中(i)aa 1是Adi和aa 4是 Glu或(ii)aa 1和a 4中的每一个为Adi,L为硫,亚砜,氧或亚甲基,该化合物(及其共轭物)与SH2结合 包含SH2结构域的未被磷酸化,在体内氧化还原稳定的蛋白质的结构域的特征在于体内相对于Grb2中的SH2结构域的小于约4.0μM的IC 50 并且在与Grb2的SH2结构域结合时具有转向构象。 包含如上所述的化合物和载体的缀合物,包含(i)如上所述的化合物或缀合物和(ii)载体的组合物,抑制包含SH2结构域的蛋白质中SH2结构域结合的方法 涉及一种动物中的靶蛋白,其中SH2结构域与靶蛋白结合抑制有效量的上述化合物或结合物接触,以及合成这种缀合物的方法。