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

Dabrafenib is an anticancer drug
currently used in the clinics,
alone or in combination. However, dabrafenib was recently shown to
potently activate the human nuclear receptor pregnane X receptor (PXR).
PXR activation increases the clearance of various chemicals and drugs,
including dabrafenib itself. It may also enhance cell proliferation
and tumor aggressiveness. Therefore, there is a need for rational
design of a potent protein kinase B-Raf inhibitor devoid of binding
to the secondary target PXR and resisting rapid metabolism. By determining
the crystal structure of dabrafenib bound to PXR and analyzing its
mode of binding to both PXR and its primary target, B-Raf-V600E, we
were able to derive new compounds with nanomolar activity against
B-Raf and no detectable affinity for PXR. The crystal structure of
B-Raf in complex with our lead compound revealed a subdomain swapping
of the activation loop with potentially important functional implications
for a prolonged inhibition of B-Raf-V600E.