Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults. With current chemotherapeutics, a positive response in patients is often not sustained, resulting in low survival rates due to relapse and drug induced toxicity. Thus, the discovery of clinically useful antitumor molecules with a novel mechanism of action is crucial for the effective long-term treatment of advanced RCC. In a National Cancer Institute Anticancer Drug Screen (NCI-60), RITA (Reactivation of p53 and Induction of Tumor cell Apoptosis, also known as NSC 652287), a heterocyclic triad composed of two thiophene and one furan rings, showed potent hyperactivity against a number of cancer cell lines with a GI50 value of about 20 nM in the renal cancer cell A498. More importantly, the triad did not impact all 60 cancer cell lines equally, indicating cell-selectivity. Although, the eact biological target of this triad is unknown, DNA-protein crosslinking and p53 activation have been proposed as possible modes of action. Structure-activity relationship (SAR) studies of RITA revealed potent analogs with either a selective or broad activity profile as determined by the NCI-60 assay. Interestingly, all new analogs were active against A498, which was among the most sensitive cell lines. A new lead analog with high potency and cell-selectivity towards A498 was discovered and may advance the potential for the clinical development of triads as therapeutic agents. Additionally, triads also serve as valuable biological tools for studying cell-selective cytotoxicity, DNA-protein crosslinking, and p53 activation. This project is aimed at exploring the chemical features and therapeutic potential of heterocyclic triads. The first SAR study will focus on the chemical stability of RITA to identify a potential mode of action. A second SAR study will further evaluate the new lead analog. Prodrug designs will be explored to improve the physical properties of the triads in order to enhance their therapeutic index. State of art protein thermal stability monitoring assays will be used to examine the literature claims of p53 binding. Successful completion of this project will provide detailed insight into the chemical features of these compounds, enabling the development of these heterocyclic triads as potential therapeutic agents for the treatment of RCC and related cancers.