We identified and developed novel selective DYRK 2 inhibitor

Dependence on the 26S proteasome is an Achilles’ heel for triplenegative
breast cancer (TNBC) andmultiplemyeloma (MM). The therapeutic
proteasome inhibitor, bortezomib, successfully targets MM
but often leads to drug-resistant disease relapse and fails in breast
cancer. Here we show that a 26S proteasome-regulating kinase,
DYRK2, is a therapeutic target for both MM and TNBC. Genome
editing or small-molecule mediated inhibition of DYRK2 significantly
reduces 26S proteasome activity, bypasses bortezomib resistance,
and dramatically delays in vivo tumor growth in MM and TNBC
thereby promoting survival. We further characterized the ability of
LDN192960, a potent and selective DYRK2-inhibitor, to alleviate tumor
burden in vivo. The drug docks into the active site of DYRK2 and
partially inhibits all 3 core peptidase activities of the proteasome.
Our results suggest that targeting 26S proteasome regulators will
pave the way for therapeutic strategies in MM and TNBC.

Multiple myeloma (MM) and triple-negative breast cancer
(TNBC) are dependent on 26S proteasome for malignancy. We
have previously shown that the proteasome-regulating kinase
DYRK2 is a viable target for both MM and TNBC. Here we
identified a specific DYRK2 inhibitor, LDN192960, which alleviates
both MM and TNBC progression via mechanisms including
partial inhibition of proteasome activity. At this time
we report a single drug target for 2 diverse cancers and highlight
the importance of identifying proteasome regulators.