Abstract
Recent advancements in therapeutic approaches targeting tyrosine kinase 2 (TYK2) have shown promising results across various medical fields, including oncology and immunology. TYK2, a Janus kinase (JAK) family member, plays a significant role in cytokine signaling and immune regulation. This Patent Highlight explores the latest developments in TYK2 inhibitors, highlighting their potential in treating diverse conditions such as cancer, alopecia areata, and psoriatic arthritis.
Important Compound Classes
Titles
Methods for Determining Responsiveness to TYK2 Inhibitors; Methods of Treating Hair-Loss Disorders with TYK2 Inhibitors; TYK2 Inhibitors and Uses Thereof; and Methods of Treating Cancer and Inhibiting TYK2 and MEK
Patent Publication Numbers
WO 2023/055901 A2 (https://patents.google.com/patent/WO2023055901A2/en?oq=:+WO+2023%2f055901+A2);
WO 2023/049241 A1 (https://patents.google.com/patent/WO2023049241A1/en?oq=WO+2023%2f049241+A1);
WO 2023/227946 A1 (URL: https://patents.google.com/patent/WO2023227946A1/en?oq=WO+2023%2f227946+A1); and
US 2023/0147873 A1 (https://patents.google.com/patent/US20230147873A1/en?oq=US+2023%2f0147873+A1)
Publication Dates
April 6, 2023; March 30, 2023; November 30, 2023; and May 11, 2023
Priority Applications
US 63/330,308; US 63/247,672; US 63/478,825; and US 63/277,331
Priority Dates
April 12, 2022; September 23, 2021; January 6, 2023; and November 9, 2021
Inventors
Hu, Y.; Gao, L.; Catlett, I. M.; Guo, X. (WO 2023/055901 A2); Catlett, I. M.; Kim, J.; Bertolini, M.; Edelkamp, J.; Rouille, T. (WO 2023/049241 A1); Pandey, A.; Dietsch, G.; Manojveer, S.; Thakkar, M.; Duraiswamy, A. J. (WO 2023/227946 A1); and Angela H.; Dana, B.; Neha, A. (US 2023/0147873 A1)
Assignee Companies
Bristol-Myers Squibb Company [US/US], Route 206 and Province Line Road, Princeton, New Jersey 08543 United States (WO 2023/055901 A2 and WO 2023/049241 A1); Sudo Biosciences Limited [GB/GB], 3rd Floor 1 Ashley Road, Altrincham, Cheshire WA14 2DT, GB (WO 2023/227946 A1); and Washington University, St. Louis, MO, United States (US 2023/0147873 A1)
Disease Area
Cancer
Biological Target
Tyrosine kinase 2 (TYK2)
Summary
Targeting tyrosine kinase 2 (TYK2) inhibitors is a significant advance in treating immune-mediated diseases due to their role in cytokine signaling pathways. Initially identified in 1990, TYK2 is a naturally occurring enzyme implicated in several immune-mediated diseases, such as psoriasis, psoriatic arthritis, and lupus. Early attempts to selectively inhibit TYK2 faced challenges. However, breakthroughs by Bristol Myers Squibb, mainly targeting the regulatory domain of TYK2, have led to successful selective inhibition. This innovative approach avoids the inhibition of other Janus kinases. It leverages the unique aspects of TYK2’s domains, marking a significant step forward in understanding and treating immune-mediated diseases. TYK2 inhibitors have emerged as a promising class of drugs due to their role in cytokine signaling pathways. These inhibitors have shown potential in treating various diseases, from autoimmune disorders to certain cancers.
The patent application US 20230147873 A1 details the innovative use of TYK2 inhibitors in cancer therapy, with a focus on malignant peripheral nerve sheath tumors (MPNSTs). This ground-breaking research illustrates the efficacy of TYK2 inhibitors, particularly in instances where TYK2 is overexpressed or mutated. The synergistic combination of TYK2 inhibitors such as deucravacitinib with MEK inhibitors like mirdametinib has been shown to effectively reduce tumor volume and enhance apoptosis in cancerous cells, marking a significant advance in targeted cancer treatments. This combination therapy represents a promising strategy for managing aggressive sarcomas, offering new hope in the fight against cancer.
Patent WO 2023049241 A1 extends the application of TYK2 inhibitors to the realm of autoimmune diseases, demonstrating their therapeutic potential beyond oncological applications. This patent highlights the effectiveness of TYK2 inhibitors in managing a range of autoimmune conditions, underscoring a significant advancement in therapeutic strategies for these disorders.
The patent application WO 2023055901 A2 unveils methods for treating psoriatic arthritis through the utilization of TYK2 inhibitors to modulate cytokine signaling, offering therapeutic advantages. Furthermore, this patent encompasses the application of TYK2 inhibitors in immune-mediated hair loss disorders such as alopecia areata, where they have been effective in both preventing and treating hair loss. This represents a significant development in the management of autoimmune conditions, highlighting the versatility and efficacy of TYK2 inhibitors in diverse clinical scenarios.
These findings highlight the usefulness of TYK2 inhibitors in addressing various autoimmune conditions. The invention also involves methods for identifying diseases in a subject susceptible to TYK2 inhibitor treatment. The disease is identified by measuring specific protein levels in the subject’s blood. The types of proteins measured to identify diseases susceptible to TYK2 inhibitor treatment include B-defensin 2 (BD2), interleukin-19 (IL-19), and interleukin-17A (IL-17A). Elevated levels of these proteins in the blood can indicate a positive response to TYK2 inhibitors, aiding in selecting suitable treatment for immune-mediated conditions. This approach enhances the precision and effectiveness of using TYK2 inhibitors in treating immune-mediated diseases.
The TYK2 inhibitors operate by modulating the JAK-STAT pathway, a critical signaling route essential in immune response and regulation of cell growth. This mechanism of action underpins their effectiveness in various therapeutic contexts, impacting both immune system behavior and cellular proliferation processes. By inhibiting TYK2, these drugs can alter cytokine signaling, thereby providing therapeutic effects in conditions where this pathway is dysregulated.
As such, TYK2 inhibitors represent a significant breakthrough in medical therapeutics, offering new treatment avenues for various diseases, including cancer and autoimmune disorders. Their ability to modulate crucial signaling pathways makes them a versatile tool in the medical arsenal. As research progresses, these inhibitors are expected to be increasingly vital in managing various health conditions.
Key Structures
Biological Assay
HEK-Blue IL-23, IFNα/β reporter assays, and HTRF-based selectivity assay.
Biological Data
The table below provides TYK2 inhibitory
activity of exemplary compounds, where A = IC50 < 30
nM and B = IC50 = 30 and 300 nM. The in vivo brain exposure studies were carried for compounds 1 and 24, which provides comprehensive insights into
their distribution and brain penetration. These investigations provided
detailed pharmacokinetic profiles, including essential brain-to-plasma
ratio data. Such information is pivotal for assessing efficacy and
safety in the context of neurological applications, providing a foundational
understanding of their potential therapeutic impact.
Recent Review Articles
The author declares no competing financial interest.
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