TNF Receptor Associated Factor 6 (TRAF6) mediates signal transductions for proteins that play roles in many diseases and conditions, including cancer and other inflammatory diseases. Small molecule inhibitors that can successfully bind to TRAF6 may be able to kill cancerous cells. Studies have already targeted CD40 to prevent the CD40L from binding; however, preventing this interaction in an upstream manner augments the problem due to downstream cells remaining inactivated. By targeting the CD40 interaction downstream at TRAF6, many side effects and other off target binding can be avoided. Compound 1a (2-(4-bromophenyl)-1-(2,4-dihydroxyphenyl)ethan-1-one) was identified as a possible TRAF6 inhibitor by Zarzycka et al. While it showed promising initial data, it had limited cytotoxicity, possibly due to electronic or steric factors. These factors could be overcome by modifications in structure. Nineteen new compounds have been identified to probe the relative cytotoxicity to TRAF6 with structural modifications by changing the bromo functionality to other functionalities. These alternate groups include electron-withdrawing, electron-donating, and bulky alkyl chains and aryl rings. With the final compounds in hand, biological activity will be assessed including a cytotoxic MTT assay on breast and cervical cancer cell lines (A549 and HeLa). Based on the results, conclusions can be drawn about what types of functional groups and electrostatics were most toxic, leading to future studies to determine specific binding to TRAF6. The results of this project will identify possible targets for pharmaceutical therapeutics but also confirm the validity of the molecular modeling data used to identify the compounds for synthesis.

Design and synthesis of novel TRAF6 inhibitors toward cancer therapeutics

ACS Spring 2022

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