Mechanism of Action
Unlike conventional PDI inhibitors or IRE1 inhibitors that target enzymatic activities and cause high toxicity, our FIC asset selectively blocks PDIA6/IRE1 PPI while preserving their biological functions, resulting in a superior safety profile.

Selective ER Stress Targeting:Exploits cancer cells' dependence on ER stress-adaptive pathways to trigger regulated cell death.
Sustained IRE1 Activation:Disrupting PDIA6/IRE1 interaction leads to IRE1-mediated cell death, overcoming traditional therapy resistance.
Low Toxicity & High Selectivity:Maintains ER homeostasis in normal cells, reducing off-target effects.

Candidate Profile

Highly Potent:Subnanomolar to low micromolar IC50s against STK11/LKB1-deficient cancer cells.
Proven In Vivo Efficacy:Dose-dependent tumor growth inhibition in multiple CDX & PDX models, with the potential for complete tumor eradication.
Oral Bioavailability & Favorable PK Profile:Demonstrates low acute toxicity and a clinically viable pharmacokinetic (PK) profile.
Synergistic Potential:Strong efficacy in combination with PARP inhibitors, proteasome inhibitors, and metabolic stressors.

Synergistic Potential

This asset can be combined with chemotherapies for STK11/LKB1-deficient patients, PARP inhibitors for PARPi-resistant cases, and proteasomeinhibitors to expand treatment indications.
This asset could extend to ATF6- and/or PERK-deficient patientsthrough synthetic lethality approaches.
Represents a blockbuster opportunityin the rapidly emerging field of ER stress/UPR-based oncology therapies.