| References: |
JNJ0966 is a highly selective compound
that inhibited activation of MMP-9 zymogen and subsequent
generation of catalytically active enzyme. JNJ0966
had no effect on MMP-1, MMP-2, MMP-3, MMP-9, or
MMP-14 catalytic activity and did not inhibit activation of
the highly related MMP-2 zymogen. The molecular basis for
this activity was characterized as an interaction of JNJ0966
with a structural pocket in proximity to the MMP-9 zymogen
cleavage site near Arg-106, which is distinct from the catalytic
domain. JNJ0966 was efficacious in reducing disease
severity in a mouse experimental autoimmune encephalomyelitis
model, demonstrating the viability of this therapeutic
approach. This discovery reveals an unprecedented pharmacological
approach to MMP inhibition, providing an opportunity
to improve selectivity of future clinical drug candidates.
Targeting zymogen activation in this manner may also
allow for pharmaceutical exploration of other enzymes previously
viewed as intractable drug targets. |
