Pharmacological inhibition of PI5P4Kα/β disrupts cell energy metabolism and selectively kills p53-null tumor cells
Abstract
Phosphatidylinositol 5-phosphate 4-kinases PI5P4Kα and PI5P4Kβ are essential for the development of late-onset tumors in mice with germline p53 deletion. The mechanism underlying their synthetic lethality was previously undefined. Here, we leverage structural insights of the lipid kinase to develop a highly potent and selective noncovalent inhibitor for PI5P4Kα/β. We show that pharmacological inhibition of PI5P4Kα/β disrupts cell energy homeostasis, causing AMPK activation and mTORC1 inhibition. Feedback through the S6K/insulin receptor substrate (IRS) loop contributes to insulin hypersensitivity and enhanced PI3K signaling. Most significantly, the energy stress induced by PI5P4Kα/β inhibition is selectively toxic toward p53-null tumor cells. The chemical probe may lead to a novel class of diabetes and cancer drugs.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- May 2021
- DOI:
- 10.1073/pnas.2002486118
- Bibcode:
- 2021PNAS..11802486C