Targeting N-Myc in Neuroblastoma with Selective Aurora Kinase A Degraders

Tang, Jian; Moorthy, Ramkumar; Demir, Özlem; Baker, Zachary D; Naumann, Jordan A.; Jones, Katherine F.; Grillo, Michael J.; Haefner, Ella S; Shi, Ke; Levy, Michaella; Aihara, Hideki; Harris, Reuben S.; Amaro, Rommie E.; Levinson, Nicholas M.; Harki, Daniel A.

doi:10.1101/2022.04.09.487756

Cited by 2 publications

(3 citation statements)

References 31 publications

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Section: Aurora-a Inhibitorsmentioning

confidence: 99%

“…Recently, the protein targeting chimeras (PROTAC) methodology has been explored for Aurora-A, with promising results [244][245][246]. Tang and colleagues developed a PROTAC from a ribociclib (CDK4/6 inhibitor) scaffold, which is able to target the Aurora-A/N-Myc complex [246]. It is worth noting that the idea of cellular pools of Aurora-A that interact in a spatially and temporally regulated manner with several partners [54] is gaining attention.…”

Section: Aurora-a Inhibitorsmentioning

confidence: 99%

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When Just One Phosphate Is One Too Many: The Multifaceted Interplay between Myc and Kinases

Boi

Rubini

Breccia

et al. 2023

IJMS

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Myc transcription factors are key regulators of many cellular processes, with Myc target genes crucially implicated in the management of cell proliferation and stem pluripotency, energy metabolism, protein synthesis, angiogenesis, DNA damage response, and apoptosis. Given the wide involvement of Myc in cellular dynamics, it is not surprising that its overexpression is frequently associated with cancer. Noteworthy, in cancer cells where high Myc levels are maintained, the overexpression of Myc-associated kinases is often observed and required to foster tumour cells’ proliferation. A mutual interplay exists between Myc and kinases: the latter, which are Myc transcriptional targets, phosphorylate Myc, allowing its transcriptional activity, highlighting a clear regulatory loop. At the protein level, Myc activity and turnover is also tightly regulated by kinases, with a finely tuned balance between translation and rapid protein degradation. In this perspective, we focus on the cross-regulation of Myc and its associated protein kinases underlying similar and redundant mechanisms of regulation at different levels, from transcriptional to post-translational events. Furthermore, a review of the indirect effects of known kinase inhibitors on Myc provides an opportunity to identify alternative and combined therapeutic approaches for cancer treatment.

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Section: Aurora-a Inhibitorsmentioning

confidence: 99%

Section: Aurora-a Inhibitorsmentioning

confidence: 99%

When Just One Phosphate Is One Too Many: The Multifaceted Interplay between Myc and Kinases

Boi

Rubini

Breccia

et al. 2023

IJMS

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“…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. [11] 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.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Aurora‐A/N‐Myc Protein–Protein Interaction Using Peptidomimetics: Understanding the Role of Peptide Cyclization**

Dawber,

Gimenez,

Batchelor

et al. 2023

ChemBioChem

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Using N‐Myc61‐89 as a starting template we showcase the systematic use of truncation and maleimide constraining to develop peptidomimetic inhibitors of the N‐Myc/Aurora‐A protein–protein interaction (PPI); a potential anticancer drug discovery target. The most promising of these – N‐Myc73‐94‐N85C/G89C‐mal, is shown to favour a more Aurora‐A compliant binding ensemble in comparison to the linear wild‐type sequence as observed through fluorescence anisotropy competition assays, circular dichroism (CD) and nuclear magnetic resonance (NMR) experiments. Further in silico investigation of this peptide in its Aurora‐A bound state, by molecular dynamics (MD) simulations, imply (i) the bound conformation is more stable as a consequence of the constraint, which likely suppresses dissociation and (ii) the constraint may make further stabilizing interactions with the Aurora‐A surface. Taken together this work unveils the first orthosteric N‐Myc/Aurora‐A inhibitor and provides useful insights on the biophysical properties and thus design of constrained peptides, an attractive therapeutic modality.

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Targeting N-Myc in Neuroblastoma with Selective Aurora Kinase A Degraders

Cited by 2 publications

References 31 publications

When Just One Phosphate Is One Too Many: The Multifaceted Interplay between Myc and Kinases

When Just One Phosphate Is One Too Many: The Multifaceted Interplay between Myc and Kinases

Inhibition of Aurora‐A/N‐Myc Protein–Protein Interaction Using Peptidomimetics: Understanding the Role of Peptide Cyclization**

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