Design and Synthesis of Ligand Efficient Dual Inhibitors of Janus Kinase (JAK) and Histone Deacetylase (HDAC) Based on Ruxolitinib and Vorinostat

Concomitant inhibition
of multiple oncogenic pathways is a desirable
goal in cancer therapy. To achieve such an outcome with a single molecule
would simplify treatment regimes. Herein the core features of ruxolitinib
(1), a marketed JAK1/2 inhibitor, have been merged with
the HDAC inhibitor vorinostat (2), leading to new molecules
that are bispecific targeted JAK/HDAC inhibitors. A preferred pyrazole
substituted pyrrolopyrimidine, 24, inhibits JAK1 and
HDACs 1, 2, 3, 6, and 10 with IC50 values of less than
20 nM, is <100 nM potent against JAK2 and HDAC11, and is selective
for the JAK family against a panel of 97 kinases. Broad cellular antiproliferative
potency of 24 is supported by demonstration of JAK-STAT
and HDAC pathway blockade in hematological cell lines. Methyl analogue 45 has an even more selective profile. This study provides
new leads for assessment of JAK and HDAC pathway dual inhibiton achieved
with a single molecule.