Development and Therapeutic Implications of Tyrosine Kinase 2 Inhibitors

by Selleckchem | Sep 19 2023

Janus kinases (JAKs) are central components in cytokine signaling pathways. A number of small molecule JAK inhibitors have been approved to treat a wide range of inflammatory and autoimmune diseases. Due to safety concerns of pan-JAK inhibition, the thrust of current research is toward the discovery of isoform-selective JAK inhibitors. Selective inhibition of tyrosine kinase 2 (TYK2) has the potential to balance efficacy and safety. Substantial efforts have been made to develop selective TYK2 inhibitors: Deucravacitinib (BMS-986165) is a representative allosteric inhibitor that has been approved by the FDA, and ropsacitinib (PF-06826647) is an active site-directed inhibitor currently being evaluated in clinical trials. Herein, we outline the key roles of TYK2 in diseases, review the advances of selective TYK2 inhibitors, and finally discuss future perspectives and challenges in the development of TYK2 inhibitors.

Comments:

Janus kinases (JAKs) play a crucial role in cytokine signaling pathways, which are involved in various inflammatory and autoimmune diseases. In recent years, several small molecule JAK inhibitors have been approved for the treatment of these conditions. However, there are safety concerns associated with broad JAK inhibition, leading researchers to focus on developing isoform-selective JAK inhibitors. One promising target is tyrosine kinase 2 (TYK2), as its selective inhibition has the potential to provide a balance between efficacy and safety.

Among the selective TYK2 inhibitors, deucravacitinib (BMS-986165) is a notable example. It is an allosteric inhibitor that has received approval from the FDA, indicating its efficacy in treating certain inflammatory diseases. Another selective TYK2 inhibitor under evaluation in clinical trials is ropsacitinib (PF-06826647). This compound is an active site-directed inhibitor and shows promise in targeting TYK2 effectively.

TYK2 plays a key role in various diseases, including psoriasis, rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosus. By specifically inhibiting TYK2, these diseases can be targeted without affecting other JAK family members, potentially reducing off-target effects.

The development of TYK2 inhibitors faces several challenges. One major hurdle is achieving selectivity, as the JAK family shares structural similarities, making it challenging to design compounds that specifically target TYK2. Additionally, the optimal balance between efficacy and safety must be achieved, as complete inhibition of TYK2 could lead to adverse effects due to its involvement in important physiological processes.

Future perspectives in TYK2 inhibitor development involve improving selectivity and reducing off-target effects. Novel drug discovery techniques, such as structure-based drug design and fragment-based approaches, may aid in developing highly selective inhibitors. Additionally, preclinical and clinical studies will be crucial for evaluating the safety and efficacy of TYK2 inhibitors in different disease contexts.

In conclusion, selective TYK2 inhibitors hold promise for the treatment of inflammatory and autoimmune diseases. While deucravacitinib has already been approved, ropsacitinib and other TYK2 inhibitors in development may further advance this field. Overcoming challenges in selectivity and safety will be important for the successful development of TYK2 inhibitors and their potential therapeutic impact.