Molecular basis of JAK kinase regulation guiding therapeutic approaches: Evaluating the JAK3 pseudokinase domain as a drug target

Anniina Virtanen; Vivian Kettunen; Kirsikka Musta; Veera Räkköläinen; Stefan Knapp; Teemu Haikarainen; Olli Silvennoinen

doi:10.1016/j.jbior.2024.101072

Molecular basis of JAK kinase regulation guiding therapeutic approaches: Evaluating the JAK3 pseudokinase domain as a drug target

Adv Biol Regul. 2024 Dec 24:101072. doi: 10.1016/j.jbior.2024.101072. Online ahead of print.

Authors

Anniina Virtanen¹, Vivian Kettunen², Kirsikka Musta², Veera Räkköläinen², Stefan Knapp³, Teemu Haikarainen⁴, Olli Silvennoinen⁵

Affiliations

¹ Faculty of Medicine and Health Technology, Tampere University, Arvo Ylpönkatu 34, 33014, Finland; Institute of Biotechnology, HiLIFE, University of Helsinki, P.O. Box 56, 00014, Finland.
² Faculty of Medicine and Health Technology, Tampere University, Arvo Ylpönkatu 34, 33014, Finland.
³ Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, 60438, Frankfurt am Main, Germany; Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Max-von-Laue-Str. 15, 60438, Frankfurt am Main, Germany.
⁴ Faculty of Medicine and Health Technology, Tampere University, Arvo Ylpönkatu 34, 33014, Finland; Department of Microbiology, Fimlab Laboratories, P.O.Box 66, 33013, Tampere, Finland.
⁵ Faculty of Medicine and Health Technology, Tampere University, Arvo Ylpönkatu 34, 33014, Finland; Institute of Biotechnology, HiLIFE, University of Helsinki, P.O. Box 56, 00014, Finland; Department of Microbiology, Fimlab Laboratories, P.O.Box 66, 33013, Tampere, Finland. Electronic address: olli.silvennoinen@tuni.fi.

PMID: 39755448
DOI: 10.1016/j.jbior.2024.101072

Abstract

Janus kinases (JAK1-3, TYK2) are critical mediators of cytokine signaling and their role in hematological and inflammatory and autoimmune diseases has sparked widespread interest in their therapeutic targeting. JAKs have unique tandem kinase structure consisting of an active tyrosine kinase domain adjacent to a pseudokinase domain that is a hotspot for pathogenic mutations. The development of JAK inhibitors has focused on the active kinase domain and the developed drugs have demonstrated good clinical efficacy but due to off-target inhibition cause also side-effects and carry a black box warning limiting their use. Our understanding of the regulatory function of the pseudokinase domain in physiological and pathological signaling has improved substantially. The pseudokinase domain maintains the inactive state of JAKs in the absence of cytokine stimulation but it has also a key role in physiological and mutation-driven activation process. Furthermore, the pseudokinase domain has favourable structural characteristics for selective targeting of cytokine signaling, such as unique mode of ATP-binding, and the first pseudokinase targeting inhibitor for TYK2 has been approved for clinical use. Here we describe the recent functional and structural knowledge of JAK signaling and their therapeutic targeting, and present data evaluating the druggability of the JAK3 pseudokinase domain.

Keywords: Cytokine signaling; Drug discovery; JAK kinase; Pseudokinase.