Identification of BRaf-Sparing Amino-Thienopyrimidines with Potent IRE1α Inhibitory Activity

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Drug Discovery

Background:

• The unfolded protein response (UPR) is a critical cellular pathway implicated in cancer.
• IRE1α is a key regulator of the UPR and a potential anticancer target.
• Amino-quinazoline BRaf kinase inhibitor 2 showed modest inhibition of IRE1α.

Purpose of the Study:

• To optimize inhibitors for potent and selective targeting of IRE1α.
• To attenuate BRaf kinase activity while enhancing IRE1α inhibition.
• To develop novel anticancer therapeutics by modulating the UPR.

Main Methods:

• Structure-based drug design utilizing crystallographic and conformational analyses.
• Systematic modification of quinazoline and thienopyrimidine scaffolds.
• Evaluation of cellular potency and selectivity against IRE1α and BRaf kinase.

Main Results:

• Quinazoline 6-position modifications improved IRE1α potency but not BRaf selectivity.
• Targeting a specific salt bridge interaction with IRE1α (Glu651) guided selectivity.
• Thienopyrimidine analogues, such as compound 25, achieved high IRE1α potency and >1000-fold BRaf inhibition decrease.

Conclusions:

• The thienopyrimidine scaffold is superior to quinazoline for achieving potent and selective IRE1α inhibition.
• Structure-based design effectively addressed selectivity challenges between IRE1α and BRaf.
• Novel thienopyrimidine derivatives represent promising drug candidates for cancer therapy targeting the UPR.