IDD388 Polyhalogenated Derivatives as Probes for an Improved Structure-Based Selectivity of AKR1B10 Inhibitors

Human
enzyme aldo-keto reductase family member 1B10 (AKR1B10) has
evolved as a tumor marker and promising antineoplastic target. It
shares high structural similarity with the diabetes target enzyme
aldose reductase (AR). Starting from the potent AR inhibitor IDD388,
we have synthesized a series of derivatives bearing the same halophenoxyacetic
acid moiety with an increasing number of bromine (Br) atoms on its
aryl moiety. Next, by means of IC50 measurements, X-ray
crystallography, WaterMap analysis, and advanced binding free energy
calculations with a quantum-mechanical (QM) approach, we have studied
their structure–activity relationship (SAR) against both enzymes.
The introduction of Br substituents decreases AR inhibition potency
but improves it in the case of AKR1B10. Indeed, the Br atoms in ortho position may impede these drugs to fit into the AR
prototypical specificity pocket. For AKR1B10, the smaller aryl moieties
of MK181 and IDD388 can bind into the external loop A subpocket. Instead,
the bulkier MK184, MK319, and MK204 open an inner specificity pocket
in AKR1B10 characterized by a π–π stacking interaction
of their aryl moieties and Trp112 side chain in the native conformation
(not possible in AR). Among the three compounds, only MK204 can make
a strong halogen bond with the protein (−4.4 kcal/mol, using
QM calculations), while presenting the lowest desolvation cost among
all the series, translated into the most selective and inhibitory
potency AKR1B10 (IC50 = 80 nM). Overall, SAR of these IDD388
polyhalogenated derivatives have unveiled several distinctive AKR1B10
features (shape, flexibility, hydration) that can be exploited to
design novel types of AKR1B10 selective drugs.