Targeting the Dark Lipid Kinase PIP4K2C with a Potent and Selective Binder and Degrader. Issue 18 (27th March 2023)

• Record Type: Journal Article
• Authors: Teng, Mingxing; Jiang, Jie; Wang, Eric S.; Geng, Qixiang; Toenjes, Sean T.; Donovan, Katherine A.; Mageed, Nada; Yue, Hong; Nowak, Radosław P.; Wang, Jinhua; Manz, Theresa D.; Fischer, Eric S.; Cantley, Lewis C.; Gray, Nathanael S.
• Is Part Of: Angewandte Chemie international edition. Volume 62:Issue 18(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-03-27
• Subjects: Degrader -- Lipid Kinase -- PI5P4Kγ -- PIP4K2C -- Protein Degradation; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.202302364
• Languages: English
• ISSNs: 1433-7851

Abstract

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. Abstract : One obstacle to a better understanding of the "dark" lipid kinase PIP4K2C is the lack of chemical tool compounds for this protein. Here, we describe a picomolar PIP4K2C binder TMX‐4102, and an effective bivalent PIP4K2C degrader, TMX‐4153, both of which display exclusive binding selectivity for PIP4K2C. Thus, TMX‐4102 and TMX‐4153 represent two useful leads to further interrogate the therapeutic potential of PIP4K2C.