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.