2. Academic Validation
  3. Targeting the Dark Lipid Kinase PIP4K2C with a Potent and Selective Binder and Degrader

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.
Mingxing Teng 1,  Jie Jiang 1,  Eric S Wang 2,  Qixiang Geng 3,  Sean T Toenjes 3,  Katherine A Donovan 1 4,  Nada Mageed 1,  Hong Yue 1 4,  Radosław P Nowak 1 4,  Jinhua Wang 1 4,  Theresa D Manz 1,  Eric S Fischer 1 4,  Lewis C Cantley 1,  Nathanael S Gray 3
Affiliations

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.
PMID: 36898968 DOI: 10.1002/anie.202302364
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.

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