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Modulation of activation-loop phosphorylation by JAK inhibitors is mode of action dependent

Radimerski, Thomas, Andraos-Rey, Rita, Qian, Zhiyan, Bonenfant, Debora, Rubert, Joelle, Vangrevelinghe, Eric, Scheufler, Clemens, Marque, Fanny, Regnier, Catherine, De Pover, Alain, Ryckelynck, Hugues, Bhagwat, Neha, Koppikar, Priya, Goel, Aviva, Wyder, Lorenza, Tavares, Gisele, Baffert, Fabienne, Pissot Soldermann, Carole, Manley, Paul W., Gaul, Christoph, Voshol, Johannes, Levine, Ross L., Sellers, William and Hofmann, Francesco (2012) Modulation of activation-loop phosphorylation by JAK inhibitors is mode of action dependent. Cancer Discovery, 2 (6). pp. 512-523. ISSN 2159-8274


JAK kinases have evolved as attractive drug targets given their roles in immune responses and hematopoiesis. JAK inhibitors are currently being developed for the treatment of rheumatoid arthritis, psoriasis, myeloproliferative neoplasms and leukemias. The vast majority of drugs being developed target the ATP-binding pocket and stabilize the active conformation of the JAK kinases. This type-I mechanism of inhibition can lead to an apparent increase in JAK activation-loop phosphorylation, despite blockage of kinase function. Here we report that stabilizing the inactive state via type-II mechanism of inhibition acts in the opposite manner, leading to a loss of activation-loop phosphorylation. We used X-ray crystallography to corroborate the binding mode and report for the first time the crystal structure of the JAK2 kinase domain in its inactive conformation. Importantly, JAK inhibitor-induced activation loop phosphorylation requires specific conformations at receptor complexes, as well as intact kinase and pseudokinase domains. Hence, depending on the respective conformation that is stabilized by a JAK inhibitor, a feed-forward response affecting the activation-loop phosphorylation sites may or may not be elicited. We conclude that further drug discovery efforts on JAK type-II inhibitors are warranted in order to assess their disease modifying potential.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14


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