Nucleophilic Inhibitors for Targeting Redox-Sensitive Kinases

描述(由申请人提供)：激酶抑制已成为开发新的抗癌疗法和研究工具化合物以剖析信号通路的主要干预点。在这项建议中，我们专注于氧化还原敏感蛋白激酶和针对这些蛋白的氧化形式的抑制剂的开发，这些蛋白在许多人类癌症中普遍存在。在目标1中，我们确定了以半胱氨酸氧化物种为目标的化学弹头。在目标2中，我们开发了以氧化酪氨酸激酶为靶点的分子，并在体外和基于癌细胞的检测中评估了它们的有效性。在目标3中，我们评估了新的激酶抑制剂的治疗效果。这项研究中确定的抑制剂将作为重要的工具来剖析激酶氧化还原调节的机制细节以及癌症中氧化应激/异常激酶活性之间的关系。此外，这些共同目标将为开发一种全新的抗癌药物奠定基础。

DESCRIPTION (provided by applicant): Kinase inhibition has emerged as the preeminent point of intervention for developing novel anti-cancer therapeutics and research tool compounds to dissect signaling pathways. In this proposal, we focus on redox- sensitive kinases and the development of inhibitors that target the oxidized form of these proteins, which are prevalent in many human cancers. In Aim 1, we identify chemical warheads that target cysteine oxidation species. In Aim 2, we develop molecules that target oxidized tyrosine kinases and evaluate their effectiveness in vitro and cancer cell-based assays. In Aim 3, we evaluate the therapeutic efficacy of new kinase inhibitors. Inhibitors identified in this study will serve as vital tools fo dissecting mechanistic details of kinase redox regulation and the relationship between oxidative stress/aberrant kinase activity in cancer. Furthermore, these collective aims will create a foundation for the development of an entirely new class of anti-cancer drugs.