Targeting the Dark Lipid Kinase PIP4K2C with a Potent and Selective Binder and Degrader.
Angew Chem Int Ed Engl
; 62(18): e202302364, 2023 04 24.
Article
em En
| MEDLINE
| ID: mdl-36898968
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.
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MEDLINE
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Autofagia
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En
Ano de publicação:
2023
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Article