Developing Novel Molecules to Down-Regulate Src Family Tyrosine Kinases

白血病和癌细胞的生物化学特性发生了改变，导致其生长速度高于正常细胞。癌症-白血病细胞的共同生化特征之一是称为酪氨酸激酶的酶的活性水平增加。参与几种癌症-白血病类型的酪氨酸激酶的主要组被称为酪氨酸激酶的Src家族。这个家族的一个成员叫林恩，多年来一直是我们的研究重点，研究它所参与的信号通路。近年来，该分子还与几种特定的白血病（慢性髓性白血病和急性髓性白血病）以及癌症（前列腺、结肠、乳腺）有关。我们已经确定了一种新的机制，下调这种酶介导的衔接分子称为Cbp，它招募林恩灭活分子Csk-Ctk以及SOCS-1，他们一起抑制林恩的活性和降解酶。利用我们对Cbp基本相互作用元件的了解，我们将设计和测试各种迷你Cbp分子在白血病和癌细胞中抑制和降解林恩的能力。这些分子可能使我们能够开发新的治疗方法，能够灭活-降解癌症和白血病中的特定酪氨酸激酶。

Leukaemia and cancer cells have altered biochemical properties resulting in their high rate of growth compared to normal cells. One of the common biochemical characteristics of cancer-leukaemia cells is augmented activity levels of enzymes called tyrosine kinases. A major group of tyrosine kinase involved in several cancer-leukaemia types is called the Src family of tyrosine kinases. One member of this family called Lyn has been our focus of study for several years, investigating the signalling pathways that it is involved in. This molecule has also been implicated in several specific leukaemia (Chronic Myeloid Leukaemia and Acute Myeloid Leukaemia) as well as cancer (Prostate, Colon, Breast) in recent years. We have identified a novel mechanism of down-regulation of this enzyme mediated by an adapter molecule called Cbp, which recruits the Lyn inactivating molecules Csk-Ctk as well as SOCS-1; together they inhibit the activity of Lyn and degrade the enzyme. Using our knowledge of the essential interaction elements of Cbp we will design and test various mini-Cbp molecules for their ability to inactivate and degrade Lyn in leukemic and cancer cells. These molecules may allow us to develop novel therapeutics capable of inactivating-degrading specific tyrosine kinases in cancer and leukaemia.