Kinases Controlling Stability of the Oncogenic MYCN Protein.
Nailah SmithEduard ReznikBrygida BisikirskaVasiliki PolychronidouQian WangArie ZaskFarhad ForouharAndrea CalifanoBrent R StockwellPublished in: ACS medicinal chemistry letters (2023)
We previously identified the natural products isopomiferin and pomiferin as powerful, indirect MYCN-ablating agents. In this work, we expand on their mechanism of action and find that casein kinase 2 (CK2), phosphoinositide 3-kinase (PI3K), checkpoint kinase 1 (CHK1) and serine/threonine protein kinase 38-like (STK38L), as well as STK38, work synchronously to create a field effect that maintains MYCN stability. By systematically inhibiting these kinases, we degraded MYCN and induced cell death. Additionally, we synthesized and tested several simpler and more cost-effective pomiferin analogues, which successfully emulated the compound's MYCN ablating activity. Our work identified and characterized key kinases that can be targeted to interfere with the stability of the MYCN protein in NBL cells, demonstrating the efficacy of an indirect approach to targeting "undruggable" cancer drivers.
Keyphrases
- protein kinase
- cell death
- cell cycle arrest
- induced apoptosis
- cancer therapy
- dna damage
- protein protein
- papillary thyroid
- amino acid
- squamous cell carcinoma
- signaling pathway
- drug delivery
- diabetic rats
- cell cycle
- transcription factor
- molecular docking
- small molecule
- endothelial cells
- molecular dynamics simulations
- pi k akt