Development of potent and selective degraders of PI5P4Kγ

Wenzhi Ji; Eric S Wang; Theresa D Manz; Jie Jiang; Katherine A Donovan; Xianmixinuer Abulaiti; Eric S Fischer; Lewis C Cantley; Tinghu Zhang; Nathanael S Gray

doi:10.1016/j.ejmech.2022.115027

Development of potent and selective degraders of PI5P4Kγ

Eur J Med Chem. 2023 Feb 5:247:115027. doi: 10.1016/j.ejmech.2022.115027. Epub 2022 Dec 24.

Authors

Affiliations

¹ Chemical and Systems Biology, Chem-H, Stanford Cancer Institute, Stanford Medicine, Stanford University, Stanford, CA, USA.
² Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
³ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
⁴ Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY, USA.
⁵ Chemical and Systems Biology, Chem-H, Stanford Cancer Institute, Stanford Medicine, Stanford University, Stanford, CA, USA. Electronic address: ztinghu8@stanford.edu.
⁶ Chemical and Systems Biology, Chem-H, Stanford Cancer Institute, Stanford Medicine, Stanford University, Stanford, CA, USA. Electronic address: nsgray01@stanford.edu.

Abstract

Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks), a family of three members in mammals (α, β and γ), have emerged as potential therapeutic targets due to their role in regulating many important cellular signaling pathways. In comparison to the PI5P4Kα and PI5P4Kβ, which usually have similar expression profiles across cancer cells, PI5P4Kγ exhibits distinct expression patterns, and pathological functions for PI5P4Kγ have been proposed in the context of cancer and neurodegenerative diseases. PI5P4Kγ has very low kinase activity and has been proposed to inhibit the PI4P5Ks through scaffolding function, providing a rationale for developing a selective PI5P4Kγ degrader. Here, we report the development and characterization of JWZ-1-80, a first-in-class PI5P4Kγ degrader. JWZ-1-80 potently degrades PI5P4Kγ via the ubiquitin-proteasome system and exhibits proteome-wide selectivity and is therefore a useful tool compound for further dissecting the biological functions of PI5P4Kγ.

Keywords: PI5P4Kγ; PROTAC; Protein degrader; Selective.

MeSH terms

Animals
Cytoplasm
Mammals*
Phosphorylation
Proteolysis

Abstract

MeSH terms

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