The Combinatorial Design of Protein Molecular Switches

描述（由申请人提供）：作为开关的蛋白质作为选择性蛋白质治疗剂具有很大的前景。PI先前的研究已经证明，蛋白质开关可以通过在两个基因之间创建大量不同的融合体并使这些基因融合体在实验室中进化来工程化。这种定向进化策略将用于开发和改进蛋白质开关，以有效地在癌细胞中选择性地激活前药。将评价这些开关使用内源性表达和通过全身递送在体内消除肿瘤异种移植物的能力。这些开关与适当的前药组合具有作为治疗癌症的靶向治疗剂的潜力。

DESCRIPTION (provided by applicant): Proteins that behave as switches hold great promise as selective protein therapeutics. Previous studies by the PI have demonstrated that protein switches can be engineered by creating a large number of different fusions between two genes and subjecting these gene fusions to evolution in the lab. Such directed evolution strategies will be used to develop and improve protein switches to effectively activate prodrugs selectively in cancer cells. These switches will be evaluated for their ability to eliminate tumor xenographs in vivo using endogenous expression and via systemic delivery. These switches in combination with the appropriate prodrug have potential as a targeted therapeutic for the treatment of cancer.