Structure-Based and Knowledge-Informed Design of B-Raf Inhibitors Devoid of Deleterious PXR Binding

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Pharmacology

Background:

• Dabrafenib, an anticancer drug, activates the pregnane X receptor (PXR).
• PXR activation can increase drug clearance and tumor aggressiveness.
• There is a need for B-Raf inhibitors that avoid PXR binding and rapid metabolism.

Purpose of the Study:

• To design potent B-Raf inhibitors lacking PXR affinity.
• To develop compounds resistant to rapid metabolism for improved efficacy.

Main Methods:

• Determined the crystal structure of dabrafenib bound to PXR.
• Analyzed binding modes to PXR and B-Raf-V600E.
• Derived and tested new compounds for B-Raf activity and PXR affinity.

Main Results:

• Developed novel compounds with nanomolar activity against B-Raf.
• These compounds showed no detectable affinity for PXR.
• Crystal structure revealed subdomain swapping in B-Raf, suggesting prolonged inhibition.

Conclusions:

• Rational drug design can yield potent B-Raf inhibitors without PXR activation.
• New compounds offer potential for improved cancer therapy by avoiding PXR-mediated drug clearance.
• Structural insights into B-Raf inhibition may lead to more effective treatments.