Acute Myeloid Leukemia (AML) is an incredibly destructive malignancy that affects around ten thousand adults and children every year. Almost 50% of patients that are treated with chemotherapeutics and bone marrow transplants experience relapse. Due to drug resistance, the clinical prognosis of patients with the relapsed disease is poor. A significant body of research has pointed to STAT3 as a promising new target for the treatment of drug-resistant tumors. Constitutive STAT3 activation prevents apoptosis, increases the drug resistance of the malignancy, and halts immune response. Inhibition of STAT3 has been shown to stop tumorgenicity. Unfortunately, like many protein-protein interactions, STAT3 interactions occur at shallow binding pockets that are difficult to inhibit effectively with traditional small-molecule approaches. Inorganic coordination to a peripheral side chain near the binding pocket has the potential to offer significantly improved potency for otherwise weakly binding ligands. Thus, we will design rhodium-containing hybrid ligands that utilize cooperativity between organic and inorganic fragments to produce a more potent STAT3 inhibitor. Initial efforts will focus on the synthesis of proposed hybrid organic-inorganic molecules. Affinity and potency will be determined via biophysical assays and by tumor growth models. Following positive in vitro results, in vivo studies will be conducted to determine the efficacy and toxicity of these novel inhibitors in living organisms.
The signal transducer and activator of transcription (STAT) proteins play crucial roles in tumor formation and progression. Inhibition of STAT pathways is a promising approach to the treatment of resistant tumors, yet traditional approaches to inhibitor development have proven ineffective. This project will develop rhodium-containing compounds that take advantage of cooperativity from organic and inorganic interactions to develop potent STAT inhibitors.