Nucleophilic Inhibitors for Targeting Redox-Sensitive Kinases

摘要 激酶抑制已成为开发新型抗癌药物的最佳干预点 治疗和研究工具化合物来剖析信号通路。在本提案中，我们关注氧化还原- 敏感的激酶和抑制剂的发展，目标是这些蛋白质的氧化形式，这是 在许多人类癌症中普遍存在。在目标1中，我们确定了针对半胱氨酸氧化的化学弹头 物种在目标2中，我们开发了靶向氧化酪氨酸激酶的分子并评估其有效性 体外和基于癌细胞的测定。在目标3中，我们评估新激酶抑制剂的治疗效果。 在这项研究中确定的抑制剂将作为解剖激酶氧化还原机制细节的重要工具 调节和癌症中氧化应激/异常激酶活性之间的关系。而且这些 集体目标将为开发全新的抗癌药物类别奠定基础。

Abstract 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 for 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.