Design and Synthesis of Janus Kinase 2 (JAK2) and Histone Deacetlyase (HDAC) Bispecific Inhibitors Based on Pacritinib and Evidence of Dual Pathway Inhibition in Hematological Cell Lines

Blockage
of more than one oncoprotein or pathway is now a standard
approach in modern cancer therapy. Multiple inhibition is typically
achieved with two or more drugs. Herein, we describe a pharmacophore
merging strategy combining the JAK2/FLT3 inhibitor pacritnib with
the pan-HDAC inhibitor, vorinostat, to create bispecific single molecules
with both JAK and HDAC targeted inhibition. A preferred ether hydroxamate, 51, inhibits JAK2 and HDAC6 with low nanomolar potency, is
<100 nM potent against HDACs 2 and 10, submicromolar potent against
HDACs 1, 8, and 11, and >50-fold selective for JAK2 in a panel
of
97 kinases. Broad cellular antiproliferative potency is supported
by demonstration of JAK-STAT and HDAC pathway blockade in several
hematological cell lines, inhibition of colony formation in HEL cells,
and analysis of apoptosis. This study provides new tool compounds
for further exploration of dual JAK–HDAC pathway inhibiton
achieved with a single molecule.