Kinases Controlling Stability of the Oncogenic MYCN Protein.

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.

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© 2023 American Chemical Society.

Déclaration de conflit d'intérêts

The authors declare the following competing financial interest(s): B.R.S. is an inventor on patents and patent applications involving ferroptosis, co-founded and serves as a consultant to ProJenX, Inc. and Exarta Therapeutics, holds equity in Sonata Therapeutics, and serves as a consultant to Weatherwax Biotechnologies Corporation and Akin Gump Strauss Hauer & Feld LLP. A.C. is founder, equity holder, and consultant of DarwinHealth Inc., a company that has licensed some of the algorithms used in this work from Columbia University. Columbia University is also an equity holder in DarwinHealth Inc.