The five-year survival rate for localized breast cancer is 99%; however, the five-year survival rate for breast cancer that has metastasized drops to 27%. Currently, there is no FDA-approved treatment to prevent the spread of these breast cancer metastases. Our collaborators and other groups have linked the role of a specific inflammatory cytokine (IC) to breast cancer metastasis, where the overexpression of the IC activates cell signaling pathways that can promote early-stage metastatic events. The IC has also been linked to other diseases, including rheumatoid arthritis, cystic fibrosis, and recently COVID-19; high IC levels in the serum of COVID-19 patients correlated with increased disease severity. The objective of this research is to design and synthesize small molecule inhibitors (SMIs) to disrupt IC-induced cell signaling. Previously, a computational screen identified SMI-26 as a potential IC inhibitor, which was confirmed upon demonstration that it inhibited IC-induced signaling pathways via enzyme-linked immunosorbent assay (ELISA). Additionally, SMI-26 analogs showed single digit micromolar binding to the IC as determined by fluorescence quenching assays. Also, preliminary results from an NMR chemical shift perturbation (CSP) assay suggest that the SMI binds at the IC/IC-receptor binding site. An initial three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was completed to ascertain structural features import for SMI binding to the IC. For the SMI-26 analogs, which are 2,4-disubstituted quinolines, it was found that favorable binding compounds contained a non-bulky group at the two position and an electron rich amide group at the four position. Recent work includes the design of SMIs based on a 2,4-disubstituted pyrimidine core that includes substituents that are added to improve drug-like properties and expand the chemical space as we search for nanomolar binding compounds. The syntheses, binding assays, and inhibition assays for the new analogs will be presented.

Design and synthesis of 2,4-disubstitued pyrimidines to inhibit a pro-metastatic cytokine

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.