Covalent Protein Binders for Cancer Research and Therapy

蛋白质-蛋白质相互作用涉及广泛的细胞功能和信号传导。各种蛋白质结合剂 已经开发出检测或调节这种相互作用以用于研究、诊断和治疗 应用.然而，现有的蛋白质结合剂通常仅以非共价模式结合其靶标， 亲和力、稳定性和完整性的限制。此外，药物与其靶标之间的共价键合 提供了超过常规药物的非共价相互作用的多种期望的治疗性质。等 近年来，共价模式已经在小分子药物中得到了很大的成功，然而， 共价蛋白质药物的治疗潜力在很大程度上仍未开发。为了改变这种范式，这个项目 将开发共价蛋白结合剂并产生共价蛋白药物。新的潜在生物活性氨基酸 将被设计和基因纳入蛋白质结合剂，这将与天然残留物的反应， 仅在蛋白质结合时靶向，选择性地在两个蛋白质之间产生稳定的共价键。 特异于免疫检查点和与癌症相关的膜受体的共价蛋白结合剂将 生成。这些共价蛋白结合剂对癌细胞信号传导和功能的独特作用将被研究。 在体外进行评估，并将评估它们作为共价蛋白药物的细胞毒活性和抗肿瘤功效 在异种移植的小鼠模型中该项目的成功将为细胞研究开辟一个新的领域 通过高度选择性、稳定和共价调节蛋白质来进行信号传导和功能。的通用平台 技术将建立共价蛋白质药物的发展，导致新一代的 用于癌症治疗的具有根本不同的结合机制的生物治疗剂。

Protein-protein interactions are involved in a broad range of cell function and signaling. Various protein binders have been developed to detect or modulate such interactions for research, diagnostic, and therapeutic applications. However, existing protein binders usually bind to their targets in noncovalent mode only, imposing limitations on affinity, stability, and completeness. In addition, covalent bonding between a drug and its target offers multiple desirable therapeutic properties over noncovalent interactions of conventional drugs. Such covalent mode has been implemented in small molecule drugs with great success in recent years, yet the therapeutic potential of covalent protein drugs remains largely untapped. To change this paradigm, this project will develop covalent protein binders and generate covalent protein drugs. New latent bioreactive amino acids will be designed and genetically incorporated into protein binders, which will react with a natural residue of the target only upon protein binding, selectively creating a stable covalent linkage between the two proteins. Covalent protein binders specific for immune-checkpoints and membrane receptors associated with cancer will be generated. The distinct effects of these covalent protein binders on cancer cell signaling and function will be assessed in vitro, and their cytotoxic activity and anti-tumor efficacy as covalent protein drugs will be evaluated in xenografted mouse models. The success of this project will instigate a new dimension for researching cell signaling and function through highly selective, stable, and covalent modulation of proteins. A general platform technology will be established for the development of covalent protein drugs, leading to a new generation of biotherapeutics with a fundamentally different binding mechanism for cancer treatment.