DISULFIDE-BOND DISRUPTING AGENTS (DDAs): NOVEL ANTICANCER AGENTS THAT DOWNREGULATE HER1–3 IN PARALLEL AND ACTIVATE THE UPR

Renan B. Ferreira¹, Mengxiong Wang², Mary E. Law², Stephan C. Jahn², Bradley J. Davis², Elham Yaaghubi¹, Amanda F. Ghilardi¹, Coy D. Heldermon³, Brian K. Law², Ronald K. Castellano¹

1Department of Chemistry, University of Florida, P.O. Box 117200, Gainesville, FL 32611-7200, USA
2Department of Pharmacology & Therapeutics, University of Florida, P.O. Box 100267, Gainesville, FL 32610-0267, USA
3Department of Medicine, University of Florida, P.O. Box 100277, Gainesville, FL 32610-0277, USA

The activation of EGFR, HER2, and HER3 initiates signaling cascades that contribute to the initiation and progression of human carcinomas, including breast and lung cancers. This fact motivated the development of inhibitors that target these receptors. However, the activity of these agents is affected by therapeutic resistance, whose important source is the functional redundancy among EGFR, HER2, and HER3. These receptors contain conserved extracellular ligand-binding domains that are stabilized by disulfide bonds. Compounds that disrupt extracellular disulfide bonds could inactivate EGFR/HER2/HER3 in unison. In this work, we identified compounds, termed Disulfide Bond Disrupting Agents (DDAs), that downregulate EGFR/HER2/HER3 and kill breast cancer cells that overexpress EGFR or HER2. RBF3, one example, exhibits anticancer efficacy in vivo at 40 mg/kg with no observed toxicity at dosages up to 160 mg/kg/day. Besides downregulation of the target receptors and Akt dephosphorylation, DDAs affect the Unfolded Protein Response (UPR), pointing to ER stress as an additional targeted pathway. New derivatives are being explored to optimize potency, study the pharmacophore tolerance upon functionalization, and create molecular probes for unveiling the DDA mechanism of action.