Structural Rationalization of IPMK Inhibitor Potency

Inositol polyphosphate multikinase (IPMK) is a kinase
linked to
several cancers; recent development of a large panel of ATP-competitive
inhibitors has reinvigorated enthusiasm for targeting IPMK. However,
the structural basis for how these inhibitors achieve high potency
is unknown. Herein, we report 14 novel cocrystal structures (1.7–2.0
resolution) of human IPMK kinase domain with these inhibitors. We
also apply a radiolabeled assay and isothermal titration calorimetry
that permit high-confidence IC50 and KD value determinations. The structures reveal a pocket
in the ATP-binding site engaged by the most potent inhibitors. Two
ordered waters also participate in hydrogen-bonding networks associated
with the most potent inhibitors. In addition to providing the molecular
basis for observed increases in potency and selectivity, the data
presented here provide a toolbelt of 14 novel inhibitor-bound structures
of human IPMK that can serve as a reference for all future IPMK structure-based
inhibitor development efforts.