Caligiuri Maureen, Molz Lisa, Liu Qing, Kaplan Faith, Xu Jimmy P, Majeti Jiangwen Z, Ramos-Kelsey Rebeca, Murthi Krishna, Lievens Sam, Tavernier Jan, Kley Nikolai
GPC Biotech Incorporated, Waltham, Massachusetts 02451, USA.
Chem Biol. 2006 Jul;13(7):711-22. doi: 10.1016/j.chembiol.2006.05.008.
Organic small molecules generally act by perturbing the function of one or more cellular target proteins, the identification of which is essential to an understanding of the molecular basis of drug action. Here we describe the application of methotrexate-linked small molecule ligands to a mammalian three-hybrid interaction trap for proteome-wide identification of small molecule targets, quantification of the targeting potency of unmodified small molecules for such targets in intact cells, and screening for inhibitors of small molecule-protein interactions. During the course of this study we also identified the pyrido[2,3-d]pyrimidine PD173955, a known SRC kinase inhibitor, as a potent inhibitor of several ephrin receptor tyrosine kinases. This finding could perhaps be exploited in the design of inhibitors for this kinase subfamily, members of which have been implicated in the pathogenesis of various diseases, including cancer.
有机小分子通常通过干扰一种或多种细胞靶蛋白的功能来发挥作用，而确定这些靶蛋白对于理解药物作用的分子基础至关重要。在此，我们描述了将甲氨蝶呤连接的小分子配体应用于哺乳动物三杂交相互作用陷阱，以进行全蛋白质组范围的小分子靶标鉴定、完整细胞中未修饰小分子对此类靶标的靶向效力定量，以及筛选小分子-蛋白质相互作用的抑制剂。在本研究过程中，我们还确定了已知的SRC激酶抑制剂吡啶并[2,3-d]嘧啶PD173955是几种 Ephrin 受体酪氨酸激酶的有效抑制剂。这一发现或许可用于设计该激酶亚家族的抑制剂，该亚家族的成员与包括癌症在内的多种疾病的发病机制有关。
