New paper reveals the broad potential of TNIK as a therapeutic target for some aging-related diseases

A new paper in Trends in Pharmacological Sciences from researchers at generative artificial intelligence (AI)- and robotics-powered clinical stage drug discovery company Insilico Medicine ("Insilico") and ETH Zurich reveals the broad potential of TNIK as a therapeutic target for some of the most pervasive aging-related diseases, including fibrosis, cancer, obesity, and Alzheimer's. The findings could guide the development of new therapeutics. The lead drug in Insilico's pipeline, INS018_055, is an AI-designed TNIK inhibitor being advanced as a treatment for the deadly lung disease idiopathic pulmonary fibrosis (IPF) and is currently in Phase II trials with patients. 

TNIK, a member of the germinal center kinase (GCK) family, has been found to play a significant role in biological processes relevant to disease states, including cell migration, cytoskeletal organization, and cell proliferation in malignant and healthy cells. 

TNIK is a reasonably novel but trending therapeutic target with around 150 papers referencing it on PubMed – most of them published since 2020. Few papers refer to it as a therapeutic target.

In cancer, TNIK has been found to drive cancer cell proliferation, treatment resistance, and cell migration across multiple cancer types – including colorectal, ovarian, thyroid, osteosarcoma, and lung squamous cell carcinoma (LSCC) – due to its activation of the Wnt signaling pathway. Aberrant Wnt signaling enhances T-cell factor 4 (TCF4) transcription factor activity and transcription of TCF4 target genes, promoting cancer cell growth and resistance to standard-of-care treatments. Targeting TNIK via an inhibitor has been shown to block these treatment-resistant properties. 

TNIK amplification is observed in a number of human cancers and has been shown to affect solid tumor progression. We see great opportunity for exploring TNIK inhibition – particularly in conjunction with other cancer agents – to improve therapeutic efficacy." 

Frank Pun, PhD, Head of Insilico Hong Kong

Researchers also looked at TNIK's role as a metabolic controller – controlling the change of dietary sugars into lipids – which could lead to TNIK inhibitors designed to combat obesity and Type 2 diabetes. The researchers speculate that TNIK could be the previously unknown regulator of DHAP-mTORC1 signaling. The protein complex mTORC1, or mammalian target of rapamycin complex 1, is the "canonical nutrient and energy sensor" the authors write, and its activation by DHAP suggests that TNIK may indirectly regulate its ability to sense glucose and coordinate de novo lipogenesis, or the metabolic formation of fat, making it a promising target for obesity. They note that when TNIK knockout (KO) mice were placed on a high-fat, high-sugar diet, the animals were resistant to diet-induced weight gain. TNIK inhibition may even contribute to increased physical activity, as the TNIK KO mice also exhibited increased activity. 

The paper also considered TNIK's emerging role in neurodegeneration. While research in this space is still in the early stages, there is a known association between neurotransmission and metabolic homeostasis, and several studies have shown TNIK's role in regulating neuronal function, including axon guidance and cell migration. There's also evidence that TNIK interacts with Tau protein, a pathogenic protein that accumulates in the brain of Alzheimer's patients, which damages neuronal signaling and neuronal repair. 

The TNIK-aging association

To understand why TNIK plays a critical role in so many diseases, the researchers point to its association with several major hallmarks of aging – in particular, chronic inflammation, deregulated nutrient sensing, cellular senescence, and altered intercellular communication.

"There is a need for high-quality targeted drugs that may address a very broad spectrum of diseases. And initiatives like the Inflation Reduction Act (IRA) provide additional incentives to go after more novel therapeutics working in multiple biological processes that can be tested in and purposed toward a broad range of diseases and have substantial combination potential," says Alex Zhavoronkov, PhD, founder and CEO of Insilico Medicine. "There are numerous examples of such therapeutics in history including aspirin and rapamycin that are very inexpensive and the new wave of comparatively safe and commercially-viable drugs targeting GLP-1, a high value therapeutic target discovered almost 40 years ago, where the breadth of therapeutic potential is still being explored. We wanted to find similar-class targets and drugs with broad therapeutic potential by looking at multiple conserved biological processes at the same time and prioritizing the data types that change significantly during aging and are implicated in age-related diseases."

Insilico researchers first identified TNIK as a therapeutic target utilizing a combination of multiple computational target discovery approaches while studying aging and fibrosis. In 2022, the Company published the hallmarks of aging assessment of multiple therapeutic targets ranked by novelty, confidence and druggability, showing that TNIK is implicated in multiple biological processes associated with aging-related diseases. 

"In 2024, we published a very important experimental paper showing several years of preclinical and clinical work on this target. In this latest paper, we are able to draw connections between aging, TNIK, and a number of diseases, including cancer, obesity and Alzheimer's," Zhavoronkov says. "This adds to our already extensive understanding of the kinase's role in fibrosis and opens the possibility for many more treatments focused on this target." 

Fibrosis, a common aging-related condition, is known to induce cellular senescence, in which cells stop dividing over time. In the case of IPF, an often fatal disease involving progressive scarring of the lungs, TNIK has been identified as a crucial profibrotic and proinflammatory agonist. Insilico's AI-designed novel inhibitor for IPF, INS018_055, meanwhile, has been shown to dramatically improve pulmonary function in rat and mice models. The drug is now in Phase II clinical trials with patients. As this AI drug progresses, it holds promise not only for IPF patients who have limited treatment options, but also potential in other aging-related disease indications. 

Source:

 InSilico Medicine                                                

Journal reference:

Ewald, C. Y., et al. (2024). TNIK’s emerging role in cancer, metabolism, and age-related diseases. Trends in Pharmacological Sciences. doi.org/10.1016/j.tips.2024.04.010.

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