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Targeting the Dark Lipid Kinase PIP4K2C with a Potent and Selective Binder and Degrader |
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| Authors: | Dr. Mingxing Teng Dr. Jie Jiang Dr. Eric S. Wang Dr. Qixiang Geng Dr. Sean T. Toenjes Dr. Katherine A. Donovan Nada Mageed Dr. Hong Yue Dr. Radosław P. Nowak Dr. Jinhua Wang Dr. Theresa D. Manz Dr. Eric S. Fischer Dr. Lewis C. Cantley Dr. Nathanael S. Gray |
| Affiliation: | 1. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215 USA;2. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215 USA These authors contributed equally to this work.;3. Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037 USA;4. Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, CA, 94305 USA;5. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215 USA 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 |