Novel Therapies in Plaque Psoriasis: A Review of Tyrosine Kinase 2 Inhibitors

by Selleckchem | Sep 18 2023

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.

Comments:

Plaque psoriasis is a systemic immune-mediated disease that is driven by interleukin-17 producing cells, which are regulated by interleukin-23. The signaling of interleukin-23 is mediated by a kinase called tyrosine kinase 2 (TYK2), which belongs to the Janus kinase family. TYK2 has emerged as a potential target for the development of oral small-molecule therapies to treat psoriasis and psoriatic arthritis.

Several TYK2 inhibitors are currently being developed or approved for the treatment of psoriasis or psoriatic arthritis. One such inhibitor is deucravacitinib, which is an oral, selective, allosteric TYK2 inhibitor. It has received approval from the US Food and Drug Administration (FDA) as a first-in-class treatment for adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. It is also approved by the Pharmaceuticals and Medical Devices Agency (PDMA) in Japan for patients with plaque psoriasis, generalized pustular psoriasis, and erythrodermic psoriasis who have not responded well to conventional therapies.

Deucravacitinib specifically binds to the regulatory pseudokinase domain of TYK2 in an allosteric manner. This binding prevents a conformational change in the catalytic domain of TYK2, which is necessary for the binding of ATP substrate. As a result, deucravacitinib effectively locks TYK2 in an inactive state.

There are two other TYK2 inhibitors, brepocitinib (PF-06700841) and ropsacitinib (PF-06826647), in later stages of clinical development. These inhibitors are orthosteric inhibitors that target the highly conserved catalytic domain of TYK2.

The selective allosteric inhibition of TYK2 by deucravacitinib may explain its improved safety profile compared to orthosteric Janus kinase (JAK) and TYK2 inhibitors. Deucravacitinib has shown efficacy in two phase 3 trials for psoriasis and has not been associated with safety concerns commonly seen with JAK inhibitors. This has led to the designation of deucravacitinib as a new class of TYK2 inhibitor by health authorities in the USA and Japan.

Allosteric TYK2 inhibitors, such as deucravacitinib, represent a promising new class of molecules for the treatment of psoriasis and psoriatic arthritis. Longer-term trials will further establish the role of these inhibitors in therapy for these conditions.