To this day, breast cancer remains the most diagnosed cancer among women; its metastasis leads to a poor prognosis, with survivability significantly decreasing from 99% with localized tumors to 28% after five years. Previous studies revealed that the overexpression of a particular inflammatory cytokine (IC) is responsible for the development of secondary tumors through the activation of signaling pathways that trigger metastatic events, including cell detachment and migration from the localized tumor to other organs. The disruption of this signaling cascade can prevent further metastasis and occurs when small molecule inhibitors (SMI) bind to the cytokine to induce conformational changes to its structure. In this study, a high-throughput virtual screen of ~1.65 million compounds was conducted in which SMI-26 demonstrated promising inhibitory activity and was chosen as a lead molecule for further investigation. SMI-26 has a quinoline core with three aromatic moieties that are being systematically optimized using a Topliss decision tree that takes into account the hydrophobic, electrostatic, and steric interactions between the SMI and IC. Thus far, we have a library of over 30 different analogs and used 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 μM. From this assay, we have determined that having an electron-withdrawing substituent in aryl group 1, an electronegative halogen substituent in aryl group 2, and a carboxylic acid in the meta position of aryl group 3 induce favorable interactions to the IC. Each analog has been tested in vitro by ELISA and at least 15 compounds have demonstrated a significant reduction in cytokine-associated signaling levels. It is envisioned that the iterative process of synthesis, analysis, and optimization will lead to improved SMI-26 candidates with binding affinities in the nanomolar range.

Synthesis and evaluation of quinoline-based small molecules as anti-metastatic agents for breast cancer

ACS Spring 2022

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