Janus kinases

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JAK - STAT signal path

Janus kinases (abbreviation JAK ) are cytoplasmic tyrosine kinases (special enzymes ), which among other cytokine - receptors are associated.

description

In contrast to receptor tyrosine kinases , cytokine receptors do not have their own enzyme activity and therefore require the kinases JAK1 and JAK2 (which was originally called "Just Another Kinase") to activate intracellular signal cascades . When a signal molecule attaches to the receptor, the JAKs are activated and then phosphorylate each other.

function

In the activated state, you can activate the so-called JAK-STAT signal path . JAKs phosphorylate so-called STAT proteins ( signal transducer and activator of transcription ). These now move to the cell nucleus , where, as transcription factors , they can stimulate the transcription of specific target genes.

Many cytokines, interferons and interleukins , but also erythropoietin , growth hormone (GH) as well as prolactin and leptin transmit their signals via the JAK and STAT proteins .

Janus kinases are named after the double-headed Roman god Janus , the guardian of the gates, as they have two similar protein domains , only one of which is functional.

Janus kinase inhibitors (JAK inhibitors)

Janus kinases can be inhibited by so-called Janus kinase inhibitors (or JAK inhibitors ) . This means that these substances ( e.g. as JAK1 inhibitors ) are kinase inhibitors . This group of substances includes a. the following substances:

  • In October 2019, the CHMP issued upadacitinib ( Rinvoq , manufacturer: AbbVie ) a positive recommendation for approval in the EU countries for the indication of rheumatoid arthritis. It was approved in the USA in August 2019.
  • Filgotinib (manufacturer: Gilead Sciences ) is currently still in phase III clinical trials in the indication rheumatoid arthritis. The application for approval for the EU was submitted in 2019. The indications of Crohn's disease and ulcerative colitis are also being investigated for filgotinib.
  • Itacitinib is an inhibitor that is more selective and more potent than JAK-2 in inhibiting JAK-1.

In contrast to other biologics such as the TNF-alpha antagonists , treatment with Janus kinase inhibitors increases the risk of reactivation of herpes zoster . In a meta-analysis there were 3.2 infections per 100 patient years. The relative risk was 2.0 for tofacitinib, 3.2 for baricitinib, and 3.0 for upadacitinib, although the exact mechanism is not known. Vaccination is therefore recommended prior to initiating therapy. A reactivation of the cytomegalovirus can also be observed, in a phase III study with ruxolitinib in 26% against 21% in the control group.

Web links

swell

  1. ↑ Joachim Rassow et al .: Duale Series - Biochemie , Thieme , 1st edition 2006, Stuttgart, page 562 ( ISBN 3-13-125351-7 ).
  2. ↑ Nicola Siegmund-Schultze: Ankylosing spondylitis. JAK1 inhibitors significantly reduce the inflammatory activity and the symptoms. In: Deutsches Ärzteblatt. Volume 117, Issue 3, January 17, 2020, p. B 72 f.
  3. ^ C. Keohane, DH Radia, CN Harrison: Treatment and management of myelofibrosis in the era of JAK inhibitors. In: Biologics. Volume 7, 2013, pp. 189-198. doi : 10.2147 / BTT.S34942 PMID 23990704 .
  4. ↑ M. Kogler: Ruxolitinib in the treatment of chronic idiopathic myelofibrosis. In: Klinik und Forschung , Volume 19, No. 1, 2013, p. 67.
  5. ↑ Summary of the EPAR for the public , EPAR of the EMA, accessed on June 14, 2018.
  6. ↑ XELJANZ® (tofacitinib citrate) Receives Marketing Authorization in the European Union for Active Psoriatic Arthritis , PM Pfizer, June 28, 2018, accessed July 4, 2018.
  7. ↑ Pfizer Announces Detailed Results of OPT Compare Phase 3 Study of Tofacitinib 5 mg and 10 mg Twice Daily Compared to High-Dose ENBREL® in Adults with Moderate-to-Severe Chronic Plaque Psoriasis , Pfizer PM March 22, 2014, accessed on March 24, 2014.
  8. ↑ Summary of opinion (post authorization) , PM EMA of April 26, 2018 (English), accessed on June 14, 2018.
  9. ↑ Summary of opinion (post authorization) , PM EMA of May 31, 2018 (English), accessed on June 14, 2018.
  10. ↑ Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) October 28-31, 2019 , PM EMA October 31, 2019, accessed November 4, 2019
  11. ↑ Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) October 14-17, 2019 , EMA PM on October 18, 2019, accessed on October 30, 2019
  12. ↑ Gilead and Galapagos Announce Efficacy and Safety Results of Filgotinib Through 52 Weeks in FINCH 1 and FINCH 3 Studies in Rheumatoid Arthritis , PM Gilead, October 10, 2019, accessed October 27, 2019
  13. ↑ Chiara Noli: Atopic dermatitis in dogs - current therapeutic approaches . In: The practical veterinarian . tape 96 , no. 10 , 2015, p. 996-1007 .
  14. ↑ Nelson Chao: Finally, a Successful Randomized Trial for GVHD New England Journal of Medicine 2020, Volume 382, ​​Issue 19 of May 7, 2020, pages 1853-1854, DOI: 10.1056 / NEJMe2003331
  15. ↑ Florian Prechter, Matthias Pletz, Ulf Müller-Ladner, Andreas Stallmach: Therapy with the downer: reactivation of herpes zoster Deutsches Ärzteblatt 2019, Volume 116, Issue 35-36 of September 2, 2019, pages A1541-1542
  16. Jump up ↑ Robert Zeiser, Nikolas von Bubnoff, Jason Butler, Mohamad Mohty, Dietger Niederwieser, Reuven Or, Jeff Szer, Eva M. Wagner, Tsila Zuckerman, Bruyère Mahuzier, Judith Xu, Celine Wilke, Kunal K. Gandhi, Gérard Socié et al. for the "REACH2 Trial Group": Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease . New England Journal of Medicine 2020, Volume 382, ​​Issue 19, May 7, 2020, pages 1800-1810, DOI: 10.1056 / NEJMoa1917635