TYK2 inhibitors are medications designed to target processes within the body that contribute to inflammation. They are used to treat certain autoimmune diseases where the immune system mistakenly attacks healthy tissues. By interfering with specific signals inside cells, TYK2 inhibitors reduce the excessive inflammation that causes disease symptoms. This approach offers a focused way to manage conditions driven by an overactive immune response.
TYK2’s Role in the Immune System
Tyrosine Kinase 2 (TYK2) is an enzyme that belongs to a family of proteins known as Janus kinases (JAKs). TYK2 plays a part in a communication network within cells called the JAK-STAT signaling pathway. This pathway acts like an internal messenger system, relaying signals from outside the cell to its nucleus.
The process begins when immune messengers, known as cytokines, bind to specialized receptors on cells. This binding causes a change in the receptor, which then activates associated JAK enzymes, including TYK2. Once activated, TYK2 and other JAKs add phosphate groups to the receptor and to signaling proteins called STATs.
These activated STAT proteins then form pairs and travel into the cell’s nucleus. Inside the nucleus, STATs bind to specific DNA sequences, instructing the cell to produce various proteins. In autoimmune conditions, this signaling can become overactive, leading to the increased production of inflammatory proteins.
Cytokines such as interleukin (IL)-12, IL-23, and type I interferons rely on TYK2 for signaling. When TYK2 is overactive, it can drive the chronic inflammation seen in certain autoimmune diseases. Therefore, interrupting TYK2’s activity can reduce this exaggerated immune response, reducing inflammation and disease symptoms.
How TYK2 Inhibitors Function
TYK2 inhibitors are small molecule drugs designed to block the TYK2 enzyme. Unlike some older medications that might broadly affect multiple immune pathways, these inhibitors are developed with precision. Their mechanism of action centers on selectivity, allowing them to target TYK2 while largely sparing other related enzymes.
Older Janus kinase (JAK) inhibitors typically bind to the active site of JAK enzymes. This active site is structurally similar across all four JAK family members (JAK1, JAK2, JAK3, and TYK2), which can lead to broader inhibition and potential off-target effects. In contrast, newer TYK2 inhibitors, such as deucravacitinib, employ a different strategy.
Deucravacitinib binds to a unique regulatory (or pseudokinase JH2) domain of the TYK2 enzyme. This domain is distinct from the active site and is not shared by other JAK family members. By binding to this specific regulatory domain, the inhibitor causes a conformational change in TYK2, effectively locking the enzyme in an inactive state.
This allosteric inhibition prevents TYK2 from functioning without directly competing at the active site where other JAKs might also bind. This specificity allows TYK2 inhibitors to block the signaling pathways mediated by IL-12, IL-23, and type I interferons, which are implicated in inflammatory diseases, while minimizing effects on pathways controlled by JAK1, JAK2, and JAK3. This targeted approach provides therapeutic benefits with a more favorable safety profile.
Conditions Treated with TYK2 Inhibitors
TYK2 inhibitors are primarily used in the treatment of autoimmune diseases characterized by an overactive immune response and inflammation. The most prominent application for this class of medication is moderate-to-severe plaque psoriasis. Deucravacitinib, marketed as Sotyktu, received its first approval in the USA in September 2022 for this specific condition in adults who are candidates for systemic therapy or phototherapy.
Plaque psoriasis is characterized by thick, red, scaly patches on the skin, resulting from rapid skin cell overproduction driven by inflammatory signals involving IL-12, IL-23, and type I interferons. Clinical trials, such as POETYK PSO-1 and POETYK PSO-2, have demonstrated that deucravacitinib significantly improves skin clearance and symptoms in patients compared to placebo and other treatments like apremilast.
Beyond plaque psoriasis, TYK2 inhibitors are being investigated for treating other autoimmune conditions. Clinical trials are exploring their use in psoriatic arthritis, a chronic inflammatory arthritis associated with psoriasis. They are also being researched for systemic lupus erythematosus (SLE), an autoimmune disease affecting many organs, including the skin.
Furthermore, inflammatory bowel disease (IBD), which includes conditions like Crohn’s disease and ulcerative colitis, is another area of active research for TYK2 inhibitors. These investigations aim to determine if targeted TYK2 inhibition can provide therapeutic benefits in these complex immune-mediated disorders, potentially expanding the range of conditions treated by this class of drugs.
Safety and Side Effects
Like all medications, TYK2 inhibitors can cause side effects, though their selective mechanism reduces broader immune suppression. The most common side effects reported in clinical studies include upper respiratory infections, like the common cold, nasopharyngitis, and sinusitis. Headaches and acne are also frequently observed mild-to-moderate adverse events.
Modulating the immune system carries a risk of increased susceptibility to infections. Serious infections have been reported in patients taking TYK2 inhibitors, though their incidence in trials has generally been low, comparable to placebo or other non-JAK oral treatments. Patients are advised not to start treatment if they have an active, serious infection.
A key distinction in the safety profile of highly selective TYK2 inhibitors, such as deucravacitinib, compared to less selective JAK inhibitors is the reduced risk of certain serious adverse events. Broader JAK inhibitors have sometimes been associated with an increased risk of major adverse cardiovascular events, blood clots (thrombosis), certain cancers, and herpes zoster (shingles). However, studies with deucravacitinib in psoriasis have indicated that the rates of these events are very low, often similar to those seen with placebo or apremilast, and do not typically lead to the same broad warnings as with non-selective JAK inhibitors.