Certain ATP-competitive Aurora-A inhibitors have been shown to perturb the N-Myc/Aurora-A interaction due to inhibitor-induced conformational changes in Aurora-A that disrupt the PPI interface; competition co-precipitation experiments found that MLN8054, but not CCT137690, disrupted the N-Myc/Aurora-A interaction. Similarly, Weiss and co-workers developed a series of conformation-disrupting Aurora-A inhibitors based on diaminopyrimidine and pyrazolopyrimidine scaffolds, such as CD532. Although CD532 was shown to be a potent N-Myc/Aurora-A inhibitor that reduced N-Myc protein levels in xenographs, concomitant inhibition of kinase activity might still perturb other cellular essential functions. An alternative approach has been to use Aurora-A degraders/PROTACS: the first-in-class Aurora-A/N-Myc degrader, HLB-0532259 was developed from a novel Aurora-A-binding ligand that engages the N-Myc/Aurora-A complex. HLB-0532259 was shown to promote degradation of Aurora-A and N-Myc with superior potency and excellent selectivity in comparison to established allosteric Aurora-A inhibitors. Despite these advances it would be desirable to have orthosteric inhibitors of N-Myc/Aurora-A interaction available as tools to dissect out the mechanistic role of this interaction and to serve as alternative leads for drug discovery. The larger PPI surface and the N-Myc helical epitope make a peptidomimetic approach attractive. Peptides have emerged as promising alternatives to small molecules given the advantages they present in terms of potent and selective target affinity; however they suffer from poor (proteolytic) stability and suboptimal cell permeability, motivating the development of constrained peptides. Here we describe the first competitive inhibitor of the N-Myc/Aurora-A interaction. Using a peptidomimetic approach we show that a truncated and constrained peptide has enhanced inhibitory potency in biophysical experiments when compared to its unconstrained analogue. This represents a starting point for development of reagents that could be used to explore inhibition of N-Myc/Aurora-A interaction for cancer chemotherapy. Moreover, using fluorescence anisotropy, circular dichroism, NMR structural analyses of the unbound peptides and molecular dynamics simulations for the Aurora-A bound peptides, we show that introduction of the constraint confers enhanced potency through a combination of subtle effects.