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    • 4. 发明授权
    • Mutant smoothened and methods of using the same
    • 突变体平滑和使用方法
    • US09321823B2
    • 2016-04-26
    • US13394069
    • 2010-09-02
    • Frederic J. de SauvageGerrit J.P. DijkgraafThomas JanuarioRobert L. Yauch
    • Frederic J. de SauvageGerrit J.P. DijkgraafThomas JanuarioRobert L. Yauch
    • C07K14/705C07K16/28
    • G01N33/74C07K14/705G01N2333/726G01N2500/10
    • The emergence of mutations in tyrosine kinases following treatment of cancer patients with molecular-targeted therapy represents a major mechanism of acquired drug resistance. Here, we describe a mutation in the serpentine receptor, Smoothened (SMO), which results in resistance to a Hedgehog (Hh) pathway inhibitor in medulloblastoma. A single amino acid substitution in a conserved aspartic acid residue of SMO maintains Hh signaling, but results in the inability of the Hh pathway inhibitor, GDC-0449, to bind SMO and suppress the pathway. This mutation was not only acquired in a GDC-0449-resistant mouse model of medulloblastoma, but was identified in a Medulloblastoma patient following relapse on GDC-0449. The invention provides screening methods to detect SMO mutations and methods to screen for drugs that specifically modulate mutant SMO exhibiting drug resistance.
    • 在分子靶向治疗癌症患者治疗后,酪氨酸激酶突变的出现代表了获得性耐药性的主要机制。 在这里,我们描述了蛇纹石受体Smoothened(SMO)中的突变,其导致对成神经管细胞瘤中的Hedgehog(Hh)通路抑制剂的抗性。 SMO的保守天冬氨酸残基中的单个氨基酸取代保持Hh信号传导,但导致Hh通路抑制剂GDC-0449不能结合SMO并抑制途径。 这种突变不仅在成神经管细胞瘤的GDC-0449抗性小鼠模型中获得,而且在GDC-0449复发后在成神经管细胞瘤患者中鉴定。 本发明提供了检测SMO突变的筛选方法和筛选特异性调节显示耐药性的突变SMO的药物的方法。
    • 5. 发明授权
    • Mutant smoothened and methods of using the same
    • 突变体平滑和使用方法
    • US08481680B2
    • 2013-07-09
    • US13253317
    • 2011-10-05
    • Frederic J. de SauvageGerrit J. P. Dijkgraaf
    • Frederic J. de SauvageGerrit J. P. Dijkgraaf
    • C07K14/00G01N33/566
    • C07K14/705C07K14/723
    • The emergence of mutations in tyrosine kinases following treatment of cancer patients with molecular-targeted therapy represents a major mechanism of acquired drug resistance. Here, we describe a mutation in the serpentine receptor, Smoothened (SMO), which results in resistance to a Hedgehog (Hh) pathway inhibitor in medulloblastoma. A single amino acid substitution in a conserved glutamic acid residue of SMO maintains Hh signaling, but results in the inability of the Hh pathway inhibitor, GDC-0449, to bind SMO and suppress the pathway. The invention provides screening methods to detect SMO mutations and methods to screen for drugs that specifically modulate mutant SMO exhibiting drug resistance.
    • 在分子靶向治疗癌症患者治疗后,酪氨酸激酶突变的出现代表了获得性耐药性的主要机制。 在这里,我们描述了蛇纹石受体Smoothened(SMO)中的突变,其导致对成神经管细胞瘤中的Hedgehog(Hh)通路抑制剂的抗性。 SMO的保守谷氨酸残基中单个氨基酸取代保持Hh信号传导,但导致Hh通路抑制剂GDC-0449不能结合SMO并抑制途径。 本发明提供了检测SMO突变的筛选方法和筛选特异性调节显示耐药性的突变SMO的药物的方法。