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Modulation of Activation-Loop Phosphorylation by JAK Inhibitors Is Binding Mode Dependent

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Modulation of Activation-Loop Phosphorylation by JAK Inhibitors Is Binding Mode Dependent Published OnlineFirst May 3, 2012; DOI: 10.1158/2159-8290.CD-11-0324 RESEARCH ARTICLE Modulation of Activation-Loop Phosphorylation by JAK Inhibitors Is Binding Mode Dependent Rita Andraos1, Zhiyan Qian1, Débora Bonenfant2, Joëlle Rubert1, Eric Vangrevelinghe3, Clemens Scheufl er4, Fanny Marque1, Catherine H. Régnier1, Alain De Pover1, Hugues Ryckelynck1, Neha Bhagwat5,6, Priya Koppikar5, Aviva Goel5, Lorenza Wyder1, Gisele Tavares4, Fabienne Baffert1, Carole Pissot-Soldermann3, Paul W. Manley3, Christoph Gaul3, Hans Voshol2, Ross L. Levine5, William R. Sellers1, Francesco Hofmann1, and Thomas Radimerski1 Downloaded from cancerdiscovery.aacrjournals.org on October 1, 2021. © 2012 American Association for Cancer Research. Published OnlineFirst May 3, 2012; DOI: 10.1158/2159-8290.CD-11-0324 ABSTRACT Janus kinase (JAK) inhibitors are being developed for the treatment of rheumatoid arthritis, psoriasis, myeloproliferative neoplasms, and leukemias. Most of these drugs target the ATP-binding pocket and stabilize the active conformation of the JAK kinases. This type I binding mode can lead to an increase in JAK activation loop phosphorylation, despite blockade of kinase function. Here we report that stabilizing the inactive state via type II 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 fi rst time the crystal structure of the JAK2 kinase domain in an inactive conformation. Importantly, JAK inhibitor–induced activation loop phosphorylation requires receptor interaction, as well as intact kinase and pseudokinase domains. Hence, depending on the respective conformation stabilized by a JAK inhibitor, hyperphosphorylation of the activation loop may or may not be elicited. SIGNIFICANCE:: This study shows that JAK inhibitors can lead to an increase of activation loop phos- phorylation in a manner that is binding mode dependent. Our results highlight the need for detailed understanding of inhibitor mechanism of action, and that it may be possible to devise strategies that avoid target priming using alternative modes of inhibiting JAK kinase activity for the treatment of JAK- dependent diseases. Cancer Discov; 2(6); 512–23. ©2012 AACR. INTRODUCTION JAK3 has emerged as a target for the prevention of transplant rejection and treatment of autoimmune diseases (10), and a JAK3- The Janus kinase (JAK) family of nonreceptor tyrosine biased inhibitor is currently undergoing evaluation in patients kinases has crucial roles in cytokine signaling and develop- with rheumatoid arthritis and other immunologic diseases. JAK2 ment. In mammals, 4 JAK family members—JAK1, JAK2, JAK3, is an important oncology target due to STAT activation in many and TYK2—have been identifi ed (1–3). The JAKs contain a cancers, recurrent translocations in leukemias creating consti- carboxyl-terminal tyrosine kinase domain and an adjacent tutively active JAK2 fusion proteins (11), and, most notably, pseudokinase domain (1), termed JAK homology (JH) 1 and activation of JAK2 through somatic mutation in polycythemia JH2 domains, respectively. It is thought that the JH2 domains vera (12). Interestingly, the latter mutation occurs within the JH2 lack protein kinase activity, although this has been challenged domain (12), exchanging valine at position 617 to phenylalanine, for the JAK2 JH2 (4), and that they may negatively regulate and is believed to disrupt the repressive function of the pseudoki- the JH1 kinase (5). However, regions of the JH2 domains seem nase. The JAK2 V617F mutation is also frequently found in the to be required for signal transduction (6, 7). Through their myeloproliferative diseases essential thrombocythemia (ET) and amino-terminal domain, the JAKs associate with cytokine primary myelofi brosis (PMF; ref. 13). receptors, which upon cytokine binding undergo a confor- Different mechanistic approaches can be taken to inhibit mational change that allows JAK activation via either auto- or protein kinases (14). The fi rst JAK inhibitors to be described transphosphorylation on tyrosine residues in the activation were the unselective tyrphostins, such as AG-490 (15), which loop (8). Subsequently, the JAKs phosphorylate cognate recep- are thought to act in a substrate-competitive manner, either tors and STAT proteins that then translocate into the nucleus non-competitive or mixed-competitive for ATP (16). More to initiate transcription of target genes (9). recently, ATP-competitive compounds binding to the kinase- active conformation (type I inhibitors) emerged as potent and 1 2 Authors’ Affi liations: Disease Area Oncology, Developmental and Molecu- selective JAK inhibitors (17, 18). Several type I JAK inhibitors lar Pathways, 3Global Discovery Chemistry, 4Center for Proteomic Chemis- try, Novartis Institutes for BioMedical Research, Basel, Switzerland; 5Human have been developed and some have shown promising activity Oncology and Pathogenesis Program and Leukemia Service, Department of in patients with rheumatoid arthritis, psoriasis, and myelofi - Medicine, Memorial Sloan-Kettering Cancer Center; and 6Gerstner Sloan- brosis (19). In contrast, type II inhibitors engage kinases in Kettering Graduate School of Biomedical Sciences, New York their inactive conformation (14). Such type II inhibitors occupy Note: Supplementary data for this article are available at Cancer Discov- a hydrophobic pocket adjacent to the ATP-binding site, which ery Online (http://cancerdiscovery.aacrjournals.org/). becomes accessible through a conformational shift of the Current address for L. Wyder: Actelion Pharmaceuticals Ltd., Allschwil, activation loop to the DFG-out state. Several type II inhibitors Switzerland. targeting either a spectrum of kinases or directed toward BCR- R. Andraos and Z. Qian contributed equally to this work. ABL have been developed for the treatment of solid tumors or Corresponding Author: Thomas Radimerski, Disease Area Oncology, chronic myeloid leukemia, respectively. To date, however, type Novartis Institutes for BioMedical Research, Klybeckstrasse 141, 4057 Basel, Switzerland. Phone: 41-61-696-20-64; Fax: 41-61-696-55-11; II inhibitors targeting JAK2 have been relatively unexplored. E-mail: [email protected] Here, we analyze the effects of JAK inhibitors having dif- doi: 10.1158/2159-8290.CD-11-0324 ferent binding modes on JAK activation loop phosphoryla- ©2012 American Association for Cancer Research. tion. Expanding on previous studies (20–22), we fi nd that JUNE 2012CANCER DISCOVERY | 513 Downloaded from cancerdiscovery.aacrjournals.org on October 1, 2021. © 2012 American Association for Cancer Research. Published OnlineFirst May 3, 2012; DOI: 10.1158/2159-8290.CD-11-0324 RESEARCH ARTICLE Andraos et al. compounds that inhibit JAKs with a type I mechanism can 1–treated HEL cells (20–22), which only express JAK2V617F and increase JAK activation loop phosphorylation, despite block- have JAK2 amplifi cation (23). Similar results were obtained ade of kinase function and inhibition of STAT phosphor- in Ba/F3 cells expressing mutant MPLW515L (Supplementary ylation. Importantly, we show that stabilizing JAKs in the Fig. S1A), which is found in up to 10% of JAK2V617F-negative inactive state by a type II inhibitor leads to the loss of activa- ET and PMF cases (25). In B-cell precursor acute lymphob- tion loop phosphorylation. The increase of JAK activation lastic leukemia (ALL) MHH-CALL-4 cells with deregulated loop phosphorylation by type I inhibitors is staurosporine- CRLF2 expression and JAK2I682F mutation (26), the different sensitive, ATP-dependent, and requires receptor interaction, JAK inhibitors suppressed STAT5 phosphorylation without as well as intact kinase and pseudokinase domains. appreciably altering JAK2 phosphorylation (Supplementary Fig. S1B). In Ba/F3 cells expressing TEL-JAK2, a cytoplas- RESULTS mic fusion protein of the oligomerization domain of TEL with the JAK2 kinase domain (27), NVP-BSK805 partially Structurally Diverse ATP-Competitive JAK Inhibitors suppressed activation loop phosphorylation (Supplemen- Can Increase JAK Activation Loop Phosphorylation tary Fig. S1C). Basal JAK2 phosphorylation was minimal in Upon profi ling JAK inhibitors in JAK2V617F-dependent SET-2 cells, but incubation with increasing concentrations SET-2 cells, which have JAK2 amplifi cation and predomi- of NVP-BSK805 increased activation loop phosphorylation, nantly express mutant JAK2 (23), we noticed an increase in reaching a plateau at concentrations of 300 nmol/L or more, JAK2 activation loop phosphorylation with JAK inhibitor which coincided with suppression of STAT5 phosphorylation exposure, despite suppression of STAT5 phosphorylation (Fig. 1B). As the JAK2 phospho-Tyr1007/Tyr1008 antibody (Fig. 1A). This phenomenon was seen with different inhibi- can cross-react with the analogous TYK2 phosphoryla- tors, including the pan-JAK inhibitor “JAK inhibitor 1” (17), tion sites, we verifi ed JAK2-specifi city by depleting JAK2 in the JAK3-biased pyrrolo[2,3-d]pyrimidine CP-690,550 (18), HEL92.1.7 cells, which seem to have largely lost dependency and the JAK2-biased quinoxaline NVP-BSK805 (24). A simi- on JAK2V617F for proliferation (28). This approach should lar disconnect between the changes in phosphorylation of avoid potential confounding effects resulting from apopto- JAK2 and STAT5 was previously observed for JAK inhibitor sis induction after JAK2 depletion in JAK2V617F-dependent Figure 1. Increase of JAK activation loop phosphorylation
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