Kinases Controlling Stability of the Oncogenic MYCN Protein
Year: 2023
Type: article
Abstract: 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.
Source: ACS Medicinal Chemistry Letters
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Defining the functions and translational potential of ferroptosis, Storage System for High Performance Computing, High Performance Computing Cluster for Biomedical Research, High-performance compute cluster for biomedical computing, Systematic Identification and Pharmacological Targeting of Tumor Dependencies for Precision Cancer Medicine, Elucidating and Targeting tumor dependencies and drug resistance determinants at the single cell level, Predicting Cancer Cell Response to Endogenous and Exogenous Perturbations at the Single Cell Level
OpenAlex ID: W4389295960