Abstract
Aurora A (AurA) kinase is a key mitotic protein implicated in cancer. Several small molecule inhibitors targeting the ATP binding site of this enzyme are in various stages of clinical development. However, these inhibitors can result in selectivity and drug resistance problems. Allosteric inhibition of kinases using small molecules is an alternative strategy to target these enzymes selectively and these could serve as the seeds for next generation medicines. This review discusses the developments in the non-ATP site binding small molecule inhibitors of AurA and their prospect as future therapeutics. Allosteric targeting of AurA kinase using small molecules is relatively a new strategy, and only a handful of research work has been reported. Two patents and three papers pertaining to allosteric targeting of AurA kinase using small molecules were covered in this review. Topics discussed include, identification of small molecule inhibitors targeting AurA- Targeting Protein for Xenopus kinesin-like protein 2 (TPX2) interaction, anacardic acid - a natural product ligand that selectively modulates AurA activity in the presence of Aurora B kinase, and identification of felodipine as an uncompetitive inhibitor of AurA using Surface Enhanced Raman Spectroscopy (SERS) technique. Allosteric targeting of therapeutically relevant enzymes using small molecules is a burgeoning research area. New techniques such as fragment-based ligand discovery, SERS methods, etc., are expanding to identify the allosteric site binding ligands. Research in this area is expected to deliver fruitful outcome in terms of novel therapeutics against AurA kinase as well as other therapeutically relevant enzymes.
Highlights
Kinases play a crucial role in signal transduction and numerous cellular processes [1, 2]
Inhibitors targeting the allosteric sites of Mitogen-Activated Protein Kinases (MAPK) discovered by this approach are in various stages of clinical trials [27,28]
Allosteric inhibition of Aurora A (AurA) has been shown to be an alternative strategy for inhibition as it is expected to have fewer off-target effects when compared with the ATP binding site targeting strategies
Summary
Kinases play a crucial role in signal transduction and numerous cellular processes [1, 2]. Targeting distant allosteric sites would be more beneficial in coming up with highly selective inhibitors which are less prone to resistance problems. Those allosteric sites could be identified and targeted by small molecules by two most common approaches. Inhibitors targeting the allosteric sites of Mitogen-Activated Protein Kinases (MAPK) discovered by this approach are in various stages of clinical trials [27,28]. A number of ATP competitive inhibitors of AurA are already in various stages of clinical development [5, 43] All these small molecules target the highly homologous ATP active site on the kinase and may result in selectivity and drug-resistance problems. There is an interest aimed at targeting allosteric inhibition sites of AurA kinase and this review summarizes the small-molecule inhibitors which have been developed to target allosteric sites of AurA kinase
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