Leveraging Click Chemistry: An Approach to Developing Small Molecule Inhibitors to Suppress the Spread of Breast Cancer
Faculty Mentor Information
Dr. Don Warner (Mentor), Boise State University
Presentation Date
7-2024
Abstract
One in eight females in the United States will develop breast cancer within their lifetime. With the occurrence of metastasis, survival rates drastically decline as much as 70%. Prior research has confirmed that overexpression of an inflammatory cytokine (IC) promotes metastasis via the activation of the JAK/STAT signaling pathway, suggesting that the IC is a promising target for repression by a small molecule inhibitor (SMI). Initial computational screenings identified quinoline-cored SMI-26 as a promising lead which is currently being optimized. A computational approach using UCFS Chimera and AutoDock Vina was used to design new analogs with increased inhibition of the IC as well as more favorable pharmacokinetic properties. Due to the high conjugation of the quinoline core, solubility was the main target for the designing of the analogs. To accomplish the synthesis of these improved analogs, a library of diverse and elaborate azides were synthesized via diazotransfers. From this, the azides were subjected to the triazole-forming azide-alkyne cycloaddition, a form of click chemistry enabling the addition of various substituents to a compound in an assembly-line fashion. The addition of heterocycles with hydrogen bonding capabilities to the azides at the is predicted to enhance the effectiveness and safety of the compound as a pharmaceutical drug.
Leveraging Click Chemistry: An Approach to Developing Small Molecule Inhibitors to Suppress the Spread of Breast Cancer
One in eight females in the United States will develop breast cancer within their lifetime. With the occurrence of metastasis, survival rates drastically decline as much as 70%. Prior research has confirmed that overexpression of an inflammatory cytokine (IC) promotes metastasis via the activation of the JAK/STAT signaling pathway, suggesting that the IC is a promising target for repression by a small molecule inhibitor (SMI). Initial computational screenings identified quinoline-cored SMI-26 as a promising lead which is currently being optimized. A computational approach using UCFS Chimera and AutoDock Vina was used to design new analogs with increased inhibition of the IC as well as more favorable pharmacokinetic properties. Due to the high conjugation of the quinoline core, solubility was the main target for the designing of the analogs. To accomplish the synthesis of these improved analogs, a library of diverse and elaborate azides were synthesized via diazotransfers. From this, the azides were subjected to the triazole-forming azide-alkyne cycloaddition, a form of click chemistry enabling the addition of various substituents to a compound in an assembly-line fashion. The addition of heterocycles with hydrogen bonding capabilities to the azides at the is predicted to enhance the effectiveness and safety of the compound as a pharmaceutical drug.