Disrupting inhibitory-kappaB kinase (IKK)-Aurora kinase signalling in prostate cancer cells

Student thesis: Doctoral Thesis

Abstract

Prostate cancer (PCa) is the second most common cause of cancer-related death in men. Aurora kinase A (AURKA) is commonly overexpressed in PCa and when active is bound to its activating cofactor, Targeting protein for Xklp2 (TPX2), preventing the dephosphorylation and degradation of AURKA. AURKA interacts with the IκB kinase (IKK) proteins, IKKα, IKKβ, and IKKγ or NF-kappa-B essential modulator (NEMO). From mapped binding studies an IKKβderived NEMO-binding domain (NBD) peptide was developed as a competitive disruptor of IKK-AURKA signalling and was hypothesised to allosterically modulate AURKA-TPX2 status. The NBD peptide in a cell-permeable (CPP) Wild-type form (WT; 100µM), also known to inhibit canonical NF-κB activation, was identified to significantly (p ZM447439 > Aurora kinase/CDK inhibitor > Aurora kinase inhibitor II > Aurora kinase inhibitor III. Hence, the NBD peptide may support two-site targeting of AURKA-TPX2 signalling, potentially improve access to the AURKA catalytic site and therefore be an advance towards pre-clinical molecules/mimetics that can potentially enhance the efficacy and clinical outcome of AURK inhibitors.
Date of Award11 Oct 2021
Original languageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsUniversity of Strathclyde
SupervisorAndrew Paul (Supervisor) & Robin Plevin (Supervisor)

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