The Epidermal Growth Factor Receptor family (HER-family) plays a key role in the initiation and progression of human cancers. Among breast cancer tumors, 25% are HER2+ and a significant portion of Triple-Negative Breast Cancer (TNBC) tumors overexpress EGFR, a potential therapeutic target still under investigation. FDA approved drugs that directly target HER2, such as monoclonal antibodies (Trastzumab and Pertuzumab), or HER2/EGFR tyrosine kinase inhibitors (Lapatinib), have significantly improved patient survival. However, the efficacy of these drugs is affected by intrinsic and/or acquired resistance. We have been studying a class of thiosulfonate molecules that have shown the ability to downregulate EGFR/HER2/HER3 in parallel and suppress their downstream signaling pathways. Due to their ability to undergo disproportionation and break disulfide bonds, these thiosulfonate molecules were named "Disulfide-bond Disrupting Agents" (DDAs). Recent studies have demonstrated that their mechanism of action involves inhibition of selected Protein Disulfide Isomerases (PDIs). DDAs also trigger the Endoplasmic Reticulum stress response and upregulate Death Receptor 5 (DR5), inducing HER2+ and EGFR+ cancer cells to undergo apoptosis. The biological response is very sensitive to structural modifications that may affect the chemical reactivity of the DDAs toward thiols; namely, their abilities to reversibly interconvert from a cyclic to a linear form. Alteration of the thiosulfonate ring size, creation of fused-ring derivatives, and substituent addition modifies the equilibrium of the ring opening/closing reactions. We are currently investigating how these structural modifications influence DDA reactions with free thiols, the energy barriers for the ring opening/closing processes, and ultimately, differences in potency against HER+ breast cancer cells. Results of computational simulations using density functional theory (DFT) and experiments will be shared along these lines. Our goal is to understand the intrinsic reactivities of the cyclic thiosulfonates and make links to biological selectivity. We are hopeful that the results may allow a more rational design of new derivatives with an ever higher anticancer activity in the future.

Structure-reactivity studies involving thiosulfonate compounds capable of selectively killing HER2+ and EGFR+ breast cancer cells

ACS Fall 2021

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