Systematic Optimization of Quinoline-Based Small Molecules to Prevent Breast Cancer Metastasis
Additional Funding Sources
This project is supported by a 2019-2020 STEM Undergraduate Research Grant from the Higher Education Research Council. Additional support was provided by Institutional Development Awards (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under Grant Nos. P20GM103408 and P20GM109095. We also acknowledge support from the Biomolecular Research Center at Boise State with funding from the National Science Foundation, Grant Nos. 0619793 and 0923535, the M.J. Murdock Charitable Trust, and the Idaho State Board of Education.
Abstract
In the year 2020, the American Cancer Society estimates that 276,480 women will be diagnosed with invasive breast cancer and 42,170 women will die in the United States alone. The five-year survival rate plummets from 99% to 27% for metastatic breast cancer patients, making breast cancer the second leading cause of cancer deaths in women. An inflammatory cytokine (IC) plays a crucial role in activating cell signaling pathways that initiate the early stages of metastasis. This research aims to develop a small molecule inhibitor (SMI) that suppresses IC-induced cell signaling. Previously, a high-throughput virtual screen of ~1.65 million compounds and a subsequent enzyme-linked immunosorbent assay (ELISA) identified SMI-26 as a promising inhibitor. The synthetic modification of the three aryl groups of SMI-26 assesses the steric, hydrophobic, and electrostatic interactions that contribute to direct binding by Fluorescence Quenching Assays and indirect binding by ELISA. This analysis has identified analogs that bind with Kd values between 40 and 2 uM— the most potent of which includes a 3-chlorophenyl moiety at the 1 position. Thus far, 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 aryl group 3 increases SMI binding to the IC.
Systematic Optimization of Quinoline-Based Small Molecules to Prevent Breast Cancer Metastasis
In the year 2020, the American Cancer Society estimates that 276,480 women will be diagnosed with invasive breast cancer and 42,170 women will die in the United States alone. The five-year survival rate plummets from 99% to 27% for metastatic breast cancer patients, making breast cancer the second leading cause of cancer deaths in women. An inflammatory cytokine (IC) plays a crucial role in activating cell signaling pathways that initiate the early stages of metastasis. This research aims to develop a small molecule inhibitor (SMI) that suppresses IC-induced cell signaling. Previously, a high-throughput virtual screen of ~1.65 million compounds and a subsequent enzyme-linked immunosorbent assay (ELISA) identified SMI-26 as a promising inhibitor. The synthetic modification of the three aryl groups of SMI-26 assesses the steric, hydrophobic, and electrostatic interactions that contribute to direct binding by Fluorescence Quenching Assays and indirect binding by ELISA. This analysis has identified analogs that bind with Kd values between 40 and 2 uM— the most potent of which includes a 3-chlorophenyl moiety at the 1 position. Thus far, 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 aryl group 3 increases SMI binding to the IC.