1. Targeting the Dark Lipid Kinase PIP4K2C with a Potent and Selective Binder and Degrader.
- Author
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Teng M, Jiang J, Wang ES, Geng Q, Toenjes ST, Donovan KA, Mageed N, Yue H, Nowak RP, Wang J, Manz TD, Fischer ES, Cantley LC, and Gray NS
- Subjects
- Autophagy
- 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., (© 2023 Wiley-VCH GmbH.)
- Published
- 2023
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