Inhibitors that stabilize a closed RAF kinase domain conformation induce dimerization.

摘要: RAF kinases have a prominent role in cancer. Their mode of activation is complex but critically requires dimerization their kinase domains. Unexpectedly, several ATP-competitive inhibitors were recently found to promote and transactivation RAS-dependent manner and, as result, undesirably stimulate RAS/ERK pathway-mediated cell growth. The mechanism by which these induce domain remains unclear. Here we describe bioluminescence resonance energy transfer-based biosensors for the extended family that enable detection living cells. Notably, demonstrate utility tools profiling selectively modulate probing structural determinants vivo. Our findings, seem generalizable other families allosterically regulated dimerization, suggest model whereby mediate stabilizing rigid closed conformation domain.