Allosteric Targeting of Aurora A Kinase Using Small Molecules: A Step Forward Towards Next Generation Medicines?

Abstract

Aurora A (AurA) kinase is a key mitotic protein essential for carrying out numerous cellular functions. Overexpression or malfunction of this enzyme results in numerous human diseases most notably in cancer. Several small molecule inhibitors targeting the ATP binding site of this enzyme are in various stages of clinical development. However, ATP binding site inhibitors can result in selectivity problems often leading to undesirable off-target effects. Moreover, these drugs are prone to drug resistance problem rendering them unfit for long-term administration. Allosteric inhibition of kinases using small molecules is an alternative strategy to target these enzymes and these could serve as the seeds for next generation medicines and minimize any selectivity problems associated with ATP binding site inhibitors. This review discusses the developments in the non-ATP site binding small molecule inhibitors of AurA and their prospect as future therapeutics and tools for chemical biology.

Research progress on the relationship between AURKA and tumorigenesis: the neglected nuclear function of AURKA

“…However, AURKA inhibitors are essentially small ATP analogs that target a highly homologous ATP-binding site (active site) on the kinase, which is highly conserved among kinase families, and targeting the ATP-binding site of the kinase can lead to poor selectivity and possible side effects in patients. In addition, kinase active site mutations are prone to lead to the emergence of drug resistance [ 94 ]. To overcome inhibitor drug resistance, researchers have studied and designed type IV inhibitors that have an altered binding site to avoid activating the kinase and instead interact with its distal allosteric site [ 95 , 96 ].…”

Allosteric Regulation of Protein Kinases Downstream of PI3-Kinase Signalling

“…A similar phenomenon and similar possibilities for allosteric modulation with small compounds are expected to take place in more evolutionary distant protein kinases where the site equivalent to the PIF-pocket or the stabilisation of the αC helix participates in the activation of kinases. Aurora A is activated by TPX2 [76,96] and was recently found to be allosterically inhibited by small compounds binding to the TPX2-binding site, which is equivalent to the PIF-pocket [97][98][99][100]. CDK7 is activated by viral cyclin T1, which precisely binds into the site equivalent to the PIF-pocket [30].…”

“…Drugs targeting the ATP-binding site that inhibit the Aurora kinase activity are of interest for the treatment of cancers. Aurora A is activated by TPX2 [76,96] in a manner that resembles the activation of PDK1 by HM polypeptides [97][98][99][100]. TPX2 provides activation and also the proper localisation of the kinase.…”

Hybrid Androgen Receptor Inhibitors Outperform Enzalutamide and EPI‐001 in in vitro Models of Prostate Cancer Drug Resistance

“…Similarly, there are extensive precedents for the success of heterobifunctional molecules, such as PROTACs, [17] bifunctional therapeutics [18] and multitarget compounds [19] . Moreover, significant efforts in moving away from conventional active site targeting have been attempted up to date [20,21] . As such, five compounds which covalently link enzalutamide and EPI‐001 with different linker lengths were synthesised in order to explore the potential dual domain inhibition.…”

“… [19] Moreover, significant efforts in moving away from conventional active site targeting have been attempted up to date. [ 20 , 21 ] As such, five compounds which covalently link enzalutamide and EPI‐001 with different linker lengths were synthesised in order to explore the potential dual domain inhibition. Various triazole‐PEG linkers were chosen, aiming to cover a range of different linker lengths.…”