Selective Tyk2 inhibitors as potential therapeutic agents: a patent review (2015–2018)

He, Xingrui; Chen, Xiabin; Zhang, Hancheng; Xie, Tian; Ye, Xiang‐Yang

doi:10.1080/13543776.2019.1567713

Cited by 65 publications

(80 citation statements)

References 42 publications

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“…Interestingly, GWAS performed on other, larger population samples for phenotypes other than TB have shown that homozygosity for TYK2 P1104A has a strong protective effect (ORs ranging from 0.1 to 0.3) against various autoinflammatory or autoimmune conditions (25,(48)(49)(50)(51)(52)(53)(54). In light of these results, the potential pharmacological benefits of TYK2 inhibitors for treating autoinflammatory or autoimmune conditions are currently being evaluated (55)(56)(57). Our findings indicate that if such treatments were to be introduced into widespread use, then it would be important to assess the risk of TB before and during treatment, as is currently done for anti-TNF immunotherapy (58).…”

Section: Discussionmentioning

confidence: 99%

Homozygosity for TYK2 P1104A underlies tuberculosis in about 1% of patients in a cohort of European ancestry

Kerner

Ramírez-Alejo

Seeleuthner

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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The human genetic basis of tuberculosis (TB) has long remained elusive. We recently reported a high level of enrichment in homozygosity for the common TYK2 P1104A variant in a heterogeneous cohort of patients with TB from non-European countries in which TB is endemic. This variant is homozygous in ∼1/600 Europeans and ∼1/5,000 people from other countries outside East Asia and sub-Saharan Africa. We report a study of this variant in the UK Biobank cohort. The frequency of P1104A homozygotes was much higher in patients with TB (6/620, 1%) than in controls (228/114,473, 0.2%), with an odds ratio (OR) adjusted for ancestry of 5.0 [95% confidence interval (CI): 1.96-10.31, P = 2 × 10 −3 ]. Conversely, we did not observe enrichment for P1104A heterozygosity, or for TYK2 I684S or V362F homozygosity or heterozygosity. Moreover, it is unlikely that more than 10% of controls were infected with Mycobacterium tuberculosis, as 97% were of European genetic ancestry, born between 1939 and 1970, and resided in the United Kingdom. Had all of them been infected, the OR for developing TB upon infection would be higher. These findings suggest that homozygosity for TYK2 P1104A may account for ∼1% of TB cases in Europeans.T uberculosis (TB) remains a major global public health problem. About a quarter of the world's population is infected with Mycobacterium tuberculosis (1, 2), resulting in ∼10 million new cases and 1.6 million deaths worldwide in 2017 (3). Nevertheless, only ∼5% of infected individuals develop active TB in their lifetime (1,4). Abundant evidence for the existence of a genetic component of TB in humans has accumulated from classic genetics studies performed from the turn of the 20th century onward, but its molecular architecture has long remained elusive (5-9). From 1996 onward, single-gene inborn errors of IFN-γ immunity have been found to underlie Mendelian susceptibility to mycobacterial disease (MSMD), which is characterized by severe disease caused by poorly virulent mycobacteria (bacillus Calmette-Guérin vaccines and environmental mycobacteria) (10-15). The clinical penetrance for MSMD depends on the genetic etiology and is inversely correlated with the levels of residual IFN-γ immunity (16). From 2001 onward, autosomal recessive interleukin-12 receptor β1 (IL-12Rβ1) and tyrosine kinase 2 (TYK2) deficiencies have also been identified in children with severe TB and without MSMD (17-23). These two deficiencies impair both the IL-12-and IL-23-dependent production of IFN-γ. They are caused by very rare (minor allele frequency, MAF <5 × 10 −5 worldwide) or private loss-of-function alleles.We recently discovered a strong enrichment in homozygosity for the common TYK2 missense variant P1104A in a genetically heterogeneous cohort of patients with TB from countries outside of Europe in which this disease is endemic, relative to ancestryadjusted controls, with an odds ratio (OR) of 89.3 (95% CI, 14.7-1,725, P = 8.37 × 10 −8 ) (24). Homozygosity for P1104A is also a genetic etiology of MSMD, albeit with much lower estimate...

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Section: Discussionmentioning

confidence: 99%

Homozygosity for TYK2 P1104A underlies tuberculosis in about 1% of patients in a cohort of European ancestry

Kerner

Ramírez-Alejo

Seeleuthner

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…JAK1 and TYK2, for the early treatment of T1D is a logical strategy. Four different JAK inhibitors have been approved for the treatment of different autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus and dermatitis 27 . Repurposing drugs that are already in use for other diseases is of great interest as the safety profiles of these molecules have already been evaluated, and this reduces the delay from the laboratory to the clinic 28 .…”

Section: Discussionmentioning

confidence: 99%

Preclinical evaluation of tyrosine kinase 2 inhibitors for human beta‐cell protection in type 1 diabetes

Brachène

Castela

Beeck

et al. 2020

Diabetes Obesity Metabolism

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Aim Type 1 diabetes (T1D) is a chronic autoimmune disease leading to progressive loss of pancreatic beta cells. Interferon (IFN)‐α plays a critical role in the crosstalk between pancreatic beta cells and the immune system in early insulitis. In human beta cells IFNα signals through JAK1 and TYK2, leading to endoplasmic reticulum stress, inflammation and HLA class I overexpression. IFNα, acting synergistically with IL‐1β, induces apoptosis. Polymorphisms in TYK2 that decrease its activity are associated with protection against T1D, and we hypothesized that pharmacological inhibitors that specifically target TYK2 could protect human beta cells against the deleterious effects of IFNα. Materials and Methods Two TYK2 inhibitors provided by Nimbus Lakshmi were tested in human insulin‐producing EndoC‐βH1 cells and human islets to evaluate their effect on IFNα signalling, beta‐cell function and susceptibility to viral infection using RT‐qPCR, western blot, immunofluorescence, ELISA and nuclear dyes. Results The two TYK2 inhibitors tested prevented IFNα‐induced human beta‐cell gene expression in a dose‐dependent manner. They also protected human islets against IFNα + IL‐1β‐induced apoptosis. Importantly, these inhibitors did not modify beta‐cell function or their survival following infection with the potential diabetogenic coxsackieviruses CVB1 and CVB5. Conclusions The two TYK2 inhibitors tested inhibit the IFNα signalling pathway in human beta cells, decreasing its pro‐inflammatory and pro‐apoptotic effects without sensitizing the cells to viral infection. The preclinical findings could pave the way for future clinical trials with TYK2 inhibitors for the prevention and treatment of type 1 diabetes.

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“…The pharmacological inhibition of TYK2 (TYK2inibs) is a recognized approach to the treatment of chronic inflammatory and autoimmune diseases and is under consideration for cancer treatment. Several TYK2inibs are in clinical trials [108,[251][252][253]. A CTLA-4-TYK2-STAT3 axis has been reported in B cell lymphoma cells and tumor-associated B cells [254] and will be relevant to immune checkpoint therapy.…”

Section: Discussionmentioning

confidence: 99%

TYK2 in Tumor Immunosurveillance

Karjalainen¹,

Shoebridge²,

Krunic³

et al. 2020

Cancers

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We review the history of the tyrosine kinase 2 (TYK2) as the founding member of the Janus kinase (JAK) family and outline its structure-function relation. Gene-targeted mice and hereditary defects of TYK2 in men have established the biological and pathological functions of TYK2 in innate and adaptive immune responses to infection and cancer and in (auto-)inflammation. We describe the architecture of the main cytokine receptor families associated with TYK2, which activate signal transducers and activators of transcription (STATs). We summarize the cytokine receptor activities with well characterized dependency on TYK2, the types of cells that respond to cytokines and TYK2 signaling-induced cytokine production. TYK2 may drive beneficial or detrimental activities, which we explain based on the concepts of tumor immunoediting and the cancer-immunity cycle in the tumor microenvironment. Finally, we summarize current knowledge of TYK2 functions in mouse models of tumor surveillance. The biology and biochemistry of JAKs, TYK2-dependent cytokines and cytokine signaling in tumor surveillance are well covered in recent reviews and the oncogenic properties of TYK2 are reviewed in the recent Special Issue ‘Targeting STAT3 and STAT5 in Cancer’ of Cancers.

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Selective Tyk2 inhibitors as potential therapeutic agents: a patent review (2015–2018)

Cited by 65 publications

References 42 publications

Homozygosity for TYK2 P1104A underlies tuberculosis in about 1% of patients in a cohort of European ancestry

Homozygosity for TYK2 P1104A underlies tuberculosis in about 1% of patients in a cohort of European ancestry

Preclinical evaluation of tyrosine kinase 2 inhibitors for human beta‐cell protection in type 1 diabetes

TYK2 in Tumor Immunosurveillance

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