Comment on: Burke et al., “Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudokinase domain.” Sci. Transl. Med. 11, eaaw1736 (2019)
Commented by: Andrea Doria, Mariele Gatto, Unit of Rheumatology, University of Padova, Italy. Email: adoria@unipd.it
The advent of small molecules in the treatment of rheumatic diseases is part of a revolution involving modulation of perturbed endogenous pathways with the aim of restoring the immune homeostasis. So far, the first generation of Janus-kinase (JAK) inhibitors comprised three agents with a main pan-JAK inhibitory effect which have shown striking efficacy in rheumatoid arthritis and psoriatic arthritis, yet at the cost of some infective side effects (1), likely related to the wide inhibition of several innate immune signaling pathways. In fact, inhibition of the JAK pathways abrogates signaling dependent on interferon (IFN, several types) and a wide array of cytokines usually involved in first line defense against infections. Importantly, first-generation JAKi are not particularly selective for one JAK over another, which is mostly due to the high sequence homology of the ATP binding site on the catalytic domain across different JAKs (also called JH1) that renders it prone to accommodate any JAKi over the regular signaling ligand. Hence, the discovery of a more selective JAKi which could maximize efficacy while minimizing infectious events is a timely challenge.
In this paper, Burke and colleagues recapitulate recent data on mechanisms and function of a novel Tyrosine Kinase (TYK2)-inhibitor throughout several autoimmune diseases including systemic lupus erythematosus (SLE).
TYK2 is part of the JAK family, yet its structure differs from those of JAKs in that TYK2 possesses a pseudokinase domain (also called JH2) preceding the true kinase catalytic domain (JH1). JH2 is thought to exert a modulatory function over JH1 through finely tuned structural changes which result in establishment of activating or inhibitory bindings between JH1-JH2 domain residues (2). TYK2 regulates signal transduction downstream receptors for IFN type I, interleukin (IL)-12 and IL-23. Interestingly, a sporadic mutation converting a proline in alanine in the catalytic domain widespread in some minorities was shown to be protective against several autoimmune diseases, including SLE, without resulting in an increased susceptibility to infections (3,4), suggesting that a selective blockade of TYK2 could be effective and safe.
Getting inspired by those observations, scientists have developed a new compound which selectively binds the ATP pocket of TYK2 on its pseudokinase domain (dissociation constant 0.02 nM), thereby providing a trans-modulation of the kinase catalytic domain. This eventually results in the very selective inhibition of TYK2 over other JAK and particularly affects pathways related to IFNalpha, as witnessed by the decreased phosphorilation of downstream STAT molecules, and IL-23 and 12, resulting in decreased production of IL-17 and IFN-gamma without significant issues in terms of susceptibility to infections as other vicariant pathways will continue to work through other receptors.
Notably, the effectiveness of inhibition of IFN-alpha, evaluated as modifications of the IFN-signature by qPCR, was remarkable among healthy human volunteers who had undergone stimulation with s.c. IFN and in lupus murine models was comparable to that provided by the IFN-receptor I (IFNAR) inhibitor, which is now in the pipeline for SLE. Additionally, a phase II randomized control trial of anti-TYK2 in lupus nephritis is about to start, in light of the preclinical data on murine models of lupus nephritis (NZB/WF1 mice) in which oral administration of anti-TYK2 (30 or 40mg/kg QD) significantly healed an already ongoing lupus-like nephritis, resulting in a remarkable clinical improvement and histological preservation of the kidneys, which was even superior to that provided by anti-IFNAR treatment.
In conclusion, there is new hope concerning use of JAKi thanks to an accumulating understanding of their function and regulation, including the knowledge that interacting with Mother Nature requires a good dose of respect beside the excitement.
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