Structure-Based Design of Selective Salt-Inducible Kinase Inhibitors

Salt-inducible kinases (SIKs) are
key metabolic regulators. The
imbalance in SIK function is associated with the development of diverse
cancers, including breast, gastric, and ovarian cancers. Chemical
tools to clarify the roles of SIK in different diseases are, however,
sparse and are generally characterized by poor kinome-wide selectivity.
Here, we have adapted the pyrido­[2,3-d]­pyrimidin-7-one-based
p21-activated kinase (PAK) inhibitor G-5555 for the targeting of SIK,
by exploiting differences in the back-pocket region of these kinases.
Optimization was supported by high-resolution crystal structures of
G-5555 bound to the known off-targets, MST3 and MST4, leading to a
chemical probe, MRIA9, with dual SIK/PAK activity and excellent selectivity
over other kinases. Furthermore, we show that MRIA9 sensitizes ovarian
cancer cells to treatment with the mitotic agent paclitaxel, confirming
earlier data from genetic knockdown studies and suggesting a combination
therapy with SIK inhibitors and paclitaxel for the treatment of paclitaxel-resistant
ovarian cancer.