HPK1 kinase inhibitor: a sufficient approach to target HPK1 to modulate T cell activation in cancer immunotherapy compared with degraders DOI Creative Commons
Qin Wang, Xinyi Zhu, Jing Li

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 6, 2025

Hematopoietic progenitor kinase 1 (HPK1) is a member of the mitogen-activated protein (MAP4K) family. It has been reported that HPK1 negatively regulates activation T cells. Several compounds have developed and tested in clinical trials to target for cancer immunotherapy. However, whether inhibition sufficient eliminate immunosuppressive function HPK1, particularly cells, remains elusive. In this study, genetic tools were used edit human lymphocyte cell line Jurkat. The HPK1-null HPK1-wildtype cells HPK1-kinase-inactive was compared through ectopic expression knockout or direct mutation. Besides validation, series selectively (with without HPK1-degradation activity) assess potential scaffold regulation primary cytotoxic activity. Augmented T-cell receptor (TCR)-induced HPK1-knockout Jurkat inhibited by complementation wildtype, but not kinase-dead HPK1. K46E-knockin K46*-knockin showed comparable levels enhanced TCR-induced with control Similarly, inhibitor (Compound 1) cereblon-based (CRBN-based) degrader 2) elicited similar degrees maximum peripheral blood summary, results study suggested may be targeting mediated

Language: Английский

HPK1 kinase inhibitor: a sufficient approach to target HPK1 to modulate T cell activation in cancer immunotherapy compared with degraders DOI Creative Commons
Qin Wang, Xinyi Zhu, Jing Li

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 6, 2025

Hematopoietic progenitor kinase 1 (HPK1) is a member of the mitogen-activated protein (MAP4K) family. It has been reported that HPK1 negatively regulates activation T cells. Several compounds have developed and tested in clinical trials to target for cancer immunotherapy. However, whether inhibition sufficient eliminate immunosuppressive function HPK1, particularly cells, remains elusive. In this study, genetic tools were used edit human lymphocyte cell line Jurkat. The HPK1-null HPK1-wildtype cells HPK1-kinase-inactive was compared through ectopic expression knockout or direct mutation. Besides validation, series selectively (with without HPK1-degradation activity) assess potential scaffold regulation primary cytotoxic activity. Augmented T-cell receptor (TCR)-induced HPK1-knockout Jurkat inhibited by complementation wildtype, but not kinase-dead HPK1. K46E-knockin K46*-knockin showed comparable levels enhanced TCR-induced with control Similarly, inhibitor (Compound 1) cereblon-based (CRBN-based) degrader 2) elicited similar degrees maximum peripheral blood summary, results study suggested may be targeting mediated

Language: Английский

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