Tyrosine kinase non-receptor 1 (TNK1) (TNK1)

Tyrosine kinase non-receptor 1 (TNK1) is a member of the ACK family of non-receptor tyrosine kinases that plays a pivotal role in regulating cell growth, survival, and immune signaling [1, 2]. It is uniquely regulated through a mechanism involving its C-terminal ubiquitin-association (UBA) domain and 14-3-3 protein binding; phosphorylation by MARK kinases promotes 14-3-3 binding to sequester and inactivate TNK1, while its release allows it to cluster in ubiquitin-rich puncta and become active [6, 8]. Although TNK1 has been identified as a tumor suppressor in some contexts—where its loss leads to spontaneous tumor formation in mice—it is frequently overactivated or mutated in various human malignancies, including Hodgkin's lymphoma, lymphoid leukemias, and solid tumors like pancreatic and lung cancer [5, 7, 17]. Beyond oncology, TNK1 is a key mediator of inflammatory responses and innate immunity, facilitating macrophage M1 polarization and enhancing JAK-STAT signaling through the phosphorylation of STAT1 [1, 4]. Additionally, TNK1 has been implicated in neurodegenerative diseases like Alzheimer's, where it may contribute to neuroinflammation and neuronal death [2, 22]. Therapeutic interest in TNK1 has led to the development of potent small-molecule inhibitors, such as TP-5801, which demonstrate significant anti-tumor activity in preclinical models by blocking TNK1-dependent signaling [7, 11, 13].

Other names

Thirty-eight negative kinase 1KOS1CD38 negative kinase 1Non-receptor tyrosine-protein kinase TNK1

Small-molecule inhibition of the TNK1 kinase domain (ATP-binding pocket), preventing the phosphorylation of downstream substrates such as STAT1 and STAT3, thereby disrupting oncogenic and pro-inflammatory signaling pathways [2, 7, 11].