EGFR / ALK / MET / ROS1 (via extracellular disulfide-bond disruption)

Class

Disulfide Bond Disrupting Agent (DDA) / redox-modulating chemosensitizer

Pathway

covalently disrupts conserved extracellular disulfide bonds on receptor tyrosine kinases and inactivates redox-regulatory enzymes that mediate drug resistance

Notes

original target text: EGFR / ALK / MET / ROS1 (via extracellular disulfide-bond disruption) plus thioredoxin/glutaredoxin/peroxiredoxin

Receptor tyrosine kinases such as EGFR, ALK, MET, and ROS1 sit on the cell surface and relay growth signals that drive cell division. Their extracellular portions are held in shape by disulfide bonds—sulfur-sulfur linkages that stabilize the protein's folding and its ability to pair up (dimerize) and become active. In many cancers these receptors are mutated or overexpressed, and tumors frequently develop resistance to drugs that block the intracellular catalytic (kinase) domain by acquiring new mutations there. A disulfide-bond-disrupting agent instead targets a structural feature shared across this receptor family, chemically breaking these bonds so the receptor cannot fold or dimerize properly, independent of which kinase-domain mutation is present. The same chemistry also inactivates redox-regulatory enzymes—thioredoxin, glutaredoxin, and peroxiredoxin—that tumor cells rely on to manage oxidative stress and that have been implicated in resistance to both targeted therapy and cytotoxic chemotherapy. By acting on a structural vulnerability rather than a catalytic one, this approach aims to restore drug sensitivity broadly across resistant tumor populations rather than requiring a new inhibitor for each emerging resistance mutation. The mechanism is relevant wherever cancers driven by these receptors eventually escape selective kinase inhibitors.