RE: GSK20 Jun 2021 11:14
Good posting Krone. A point of interest here:-
The exact impact of JAK inhibitors on a wider spectrum of activation states of macrophages is however still to be determined, especially in the context of disorders involving concomitant activation of pro-inflammatory M1 macrophages and profibrotic M2 macrophages.
I do recall Tim in the early stages approx 12 month ago in one of his presentations stating his reasonings as to why a Tyk2 and Jak 1 inhibitor would likely be more effective than than Jak2 and Jak 3 inhibitors. My understanding is:-
Jak 2 and Jak 3 have a much broader spectrum than Tyk 2. Tyk 2 is far more selective. Jak2 and Jak3 combined press all the right buttons and some of the wrong buttons which then prove to be counterproductive. Tyk2 has all the advantages of Jak2 and in addition greater selectivity. Jak3 reacts with too many enzymes.
Deficiency of JAK3 blocks signaling of the following cytokines and their effects:[9]
IL-2 - T cell proliferation and maintenance of peripheral tolerance
IL-4 - differentiation of Th2 cells
IL-7 - thymocyte development in the thymus
IL-9 - survival signal for various hematopoietic cells
IL-15 - NK cell development
IL-21 - regulation of immunoglobulin class switching in B cells
Since JAK3 is required for immune cell development, targeting JAK3 could be a useful strategy to generate a novel class of immunosuppressant drugs. Moreover, unlike other JAKs, JAK3 is primarily expressed in hematopoietic cells, so a highly specific JAK3 inhibitor should have precise effects on immune cells and minimal pleiotropic defects.[9] The selectivity of a JAK3 inhibitor would also have advantages over the current widely used immunosuppressant drugs, which have abundant targets and diverse side effects. A JAK3 inhibitor could be useful for treating autoimmune diseases, especially those in which a particular cytokine receptor has a direct role on disease pathogenesis. For example, signaling through the IL-15 receptor is known to be important in the development rheumatoid arthritis,[27] and the receptors for IL-4 and IL-9 play roles in the development of allergic responses.
JAK3 is activated only by cytokines whose receptors contain the common gamma chain (?c) subunit: IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21.
No mention in the report of Jak1 or Tyk2 ( wonders why)
With regards to Jak1 and I believe this to be advantageous in SDC1801
Also, one study indicates that JAK1 is needed to carry out signalling for receptors of the cytokines IFN?, IL-2, IL-4 and IL-10.['
in addition
Selective inhibition of JAK3, JAK1 or Tyk2 provides the opportunity to achieve clinical efficacy in the treatment of inflammatory diseases while reducing the risk of dose-limiting effects attributable to JAK2 inhibition.'
Apologies if appears a little disorganised, called into work early
Regards
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