ITK degradation to block T cell receptor signaling and overcome therapeutic resistance in T cell lymphomas

Baishan Jiang; David M Weinstock; Katherine A Donovan; Hong-Wei Sun; Ashley Wolfe; Sam Amaka; Nicholas L Donaldson; Gongwei Wu; Yuan Jiang; Ryan A Wilcox; Eric S Fischer; Nathanael S Gray; Wenchao Wu

doi:10.1016/j.chembiol.2023.03.007

ITK degradation to block T cell receptor signaling and overcome therapeutic resistance in T cell lymphomas

Cell Chem Biol. 2023 Apr 20;30(4):383-393.e6. doi: 10.1016/j.chembiol.2023.03.007. Epub 2023 Apr 3.

Authors

Affiliations

¹ Department of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.
³ 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.
⁴ Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital, Jinan University, Zhuhai, China.
⁵ Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA.
⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
⁸ Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, CA 94305, USA. Electronic address: nsgray01@stanford.edu.
⁹ Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. Electronic address: wuwch@sysucc.org.cn.

Abstract

Interleukin (IL)-2-inducible T cell kinase (ITK) is essential for T cell receptor (TCR) signaling and plays an integral role in T cell proliferation and differentiation. Unlike the ITK homolog BTK, no inhibitors of ITK are currently US Food and Drug Administration (FDA) approved. In addition, recent studies have identified mutations within BTK that confer resistance to both covalent and non-covalent inhibitors. Here, as an alternative strategy, we report the development of BSJ-05-037, a potent and selective heterobifunctional degrader of ITK. BSJ-05-037 displayed enhanced anti-proliferative effects relative to its parent inhibitor BMS-509744, blocked the activation of NF-kB/GATA-3 signaling, and increased the sensitivity of T cell lymphoma cells to cytotoxic chemotherapy both in vitro and in vivo. In summary, targeted degradation of ITK is a novel approach to modulate TCR signal strength that could have broad application for the investigation and treatment of T cell-mediated diseases.

Keywords: GATA-3; ITK; PROTAC; T cell lymphoma; TCR signaling.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Drug Resistance, Neoplasm
Humans
Lymphoma, T-Cell* / drug therapy
Receptors, Antigen, T-Cell / metabolism
Signal Transduction*
T-Lymphocytes

Substances

Receptors, Antigen, T-Cell

Abstract

Publication types

MeSH terms

Substances

Grants and funding