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.
Oxidative stress and deregulation of protein kinase activity play significant roles in the development and progression of cancer. Successful covalent inhibitors have been developed that interact with the amino acids cysteine or lysine in proteins, however off-target interactions remain a significant problem. Here, we propose a new chemical strategy to make inhibitors that retains the specific advantages gained through covalent targeting and decrease the potential for off-target activity. These new inhibitors will provide an important starting point for the development of new anti-cancer drugs.
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