Targeting the Dark Lipid Kinase PIP4K2C with a Potent and Selective Binder and Degrader

Mingxing Teng; Jie Jiang; Eric S Wang; Qixiang Geng; Sean T Toenjes; Katherine A Donovan; Nada Mageed; Hong Yue; Radosław P Nowak; Jinhua Wang; Theresa D Manz; Eric S Fischer; Lewis C Cantley; Nathanael S Gray

doi:10.1002/anie.202302364

Targeting the Dark Lipid Kinase PIP4K2C with a Potent and Selective Binder and Degrader

Angew Chem Int Ed Engl. 2023 Apr 24;62(18):e202302364. doi: 10.1002/anie.202302364. Epub 2023 Mar 27.

Authors

Mingxing Teng¹, Jie Jiang¹, Eric S Wang², Qixiang Geng³, Sean T Toenjes³, Katherine A Donovan^{1

4}, Nada Mageed¹, Hong Yue^{1

4}, Radosław P Nowak^{1

4}, Jinhua Wang^{1

4}, Theresa D Manz¹, Eric S Fischer^{1

4}, Lewis C Cantley¹, Nathanael S Gray³

Affiliations

¹ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
² Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
³ Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, CA, 94305, USA.
⁴ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.

Abstract

Phosphatidylinositol 5-phosphate 4-kinase, type II, gamma (PIP4K2C) remains a poorly understood lipid kinase with minimal enzymatic activity but potential scaffolding roles in immune modulation and autophagy-dependent catabolism. Achieving potent and selective agents for PIP4K2C while sparing other lipid and non-lipid kinases has been challenging. Here, we report the discovery of the highly potent PIP4K2C binder TMX-4102, which shows exclusive binding selectivity for PIP4K2C. Furthermore, we elaborated the PIP4K2C binder into TMX-4153, a bivalent degrader capable of rapidly and selectively degrading endogenous PIP4K2C. Collectively, our work demonstrates that PIP4K2C is a tractable and degradable target, and that TMX-4102 and TMX-4153 are useful leads to further interrogate the biological roles and therapeutic potential of PIP4K2C.

Keywords: Degrader; Lipid Kinase; PI5P4Kγ; PIP4K2C; Protein Degradation.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Autophagy*

Abstract

Publication types

MeSH terms

Grants and funding