Synthesis and Evaluation of 2,4,6-Trisubstituted Quinoline Small Molecules to Inhibit a Notorious Inflammatory Cytokine
Dr. Don L. Warner
The American Cancer Society estimates the five-year survival rate for women with localized breast cancer is 99%. However, the rate plummets to 28% for patients whose cancer metastasized –tumor cells spread throughout the body to form new tumors in distant organs—and currently, there are no FDA-approved therapeutics to prevent metastasis. Previous studies have elucidated an inflammatory cytokine (IC) plays a crucial role in the activation of cell signaling pathways that initiate the early stages of metastasis. Several similar studies have implicated the IC as an inflammatory mediator in other diseases such as Rheumatoid Arthritis, Lung Fibrosis, and most recently, COVID-19, in which overexpression of the IC correlated with increased clinical COVID-19 disease severity. The purpose of this research is to develop novel small molecule inhibitors (SMIs) that suppress the IC-induced cell signaling through direct binding. A prior computational high-throughput screen of ~1.65 million compounds identified SMI-26 as a promising IC inhibitor and amenable to optimization to improve activity. Thus far, we synthesized 33 different analogs and utilized fluorescence quenching assays to determine the binding affinity (KD) of the SMI analogs to the IC. This analysis has identified analogs that bind with KD values between 40 and 2 mM. Each SMI has been tested in vitro by Enzyme-Linked Immunosorbent Assays (ELISAs), and at least 16 analogs exhibited significant inhibitory activity. The incorporation of a single electron-withdrawing substituent in aryl group 1, an electronegative halogen moiety in aryl group 2, and a carboxylic acid in the meta position in aryl group 3 have been shown to increase SMI binding affinity to the target IC. Further characterization and optimization of SMI analogs are underway, and it is envisioned that this iterative analysis will lead to improved SMI candidates with binding affinities in the nanomolar range.
Coughlin, Grace; Conrad, Thomas; Lighter, Darren; Muhammed, Thaaer; Wolf, Cody; Jorcyk, Cheryl; Warner, Lisa R.; King, Matthew; and Warner, Don L., "Synthesis and Evaluation of 2,4,6-Trisubstituted Quinoline Small Molecules to Inhibit a Notorious Inflammatory Cytokine" (2021). 2021 Undergraduate Research Showcase. 157.