We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Novel Therapies in Plaque Psoriasis: A Review of Tyrosine Kinase 2 Inhibitors.
- Authors
Martin, George
- Abstract
Plaque psoriasis is a systemic immune-mediated disease driven by interleukin-17 producing cells under the regulation of interleukin-23. Interleukin-23 signaling is mediated by the intracellular kinase tyrosine kinase 2, a Janus kinase family member. Tyrosine kinase 2 is a potential target for oral small-molecule therapies to treat psoriasis and psoriatic arthritis. A number of tyrosine kinase 2 inhibitors are in development or approved for the treatment of psoriasis or psoriatic arthritis. Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved by the US Food and Drug Administration as a first-in-class treatment for adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy, and is approved by Pharmaceuticals and Medical Devices Agency (PDMA) in Japan for patients with plaque psoriasis, generalized pustular psoriasis, and erythrodermic psoriasis who have had an inadequate response to conventional therapies. Deucravacitinib selectively binds to the unique tyrosine kinase 2 regulatory pseudokinase domain in an allosteric fashion, preventing a conformational change in the catalytic domain required for ATP substrate binding, thus effectively locking tyrosine kinase 2 in an inactive state. Two other tyrosine kinase 2 inhibitors in later stage clinical development, brepocitinib (PF-06700841) and ropsacitinib (PF-06826647), are orthosteric inhibitors that target the highly conserved catalytic domain. This selective allosteric tyrosine kinase 2 inhibition may explain the improved safety profile of deucravacitinib versus orthosteric Janus kinase and tyrosine kinase 2 inhibitors. Two phase 3 psoriasis trials demonstrated deucravacitinib was efficacious and not associated with safety concerns characteristic of Janus kinase inhibitors, hence the new class designation (TYK2 inhibitor) by health authorities in the USA and Japan. Allosteric tyrosine kinase 2 inhibitors represent a promising new class of molecules for the treatment of psoriasis and psoriatic arthritis, and longer-term trials will establish their place in therapy.
- Subjects
JAPAN; KINASES; PROTEIN-tyrosine kinase inhibitors; PROTEIN-tyrosine kinases; PSORIASIS; PSORIATIC arthritis; CLINICAL trials
- Publication
Dermatology & Therapy, 2023, Vol 13, Issue 2, p417
- ISSN
2193-8210
- Publication type
Article
- DOI
10.1007/s13555-022-00878-9