{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T07:31:55Z","timestamp":1778657515309,"version":"3.51.4"},"reference-count":65,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,11,8]],"date-time":"2019-11-08T00:00:00Z","timestamp":1573171200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,11,8]],"date-time":"2019-11-08T00:00:00Z","timestamp":1573171200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Ruxolitinib is a type I JAK inhibitor approved by FDA for targeted therapy of Philadelphia-negative myeloproliferative neoplasms (MPNs), all characterized by mutations activating the JAK2\/STAT signaling pathway. Treatment with ruxolitinib improves constitutional symptoms and splenomegaly. However, patients can become resistant to treatment and chronic therapy has only a mild effect on molecular\/pathologic remissions. Drugs interaction with plasma proteins, <jats:italic>i.e<\/jats:italic>. human serum albumin (HSA), is an important factor affecting the intensity and duration of their pharmacological actions. Here, the ruxolitinib recognition by the fatty acid binding sites (FAs) 1, 6, 7, and 9 of HSA has been investigated from the bioinformatics, biochemical and\/or biological viewpoints. Docking simulations indicate that ruxolitinib binds to multiple sites of HSA. Ruxolitinib binds to the FA1 and FA7 sites of HSA with high affinity (<jats:italic>K<\/jats:italic><jats:sub>r<\/jats:sub>\u2009=\u20093.1\u2009\u03bcM and 4.6\u2009\u03bcM, respectively, at pH 7.3 and 37.0\u2009\u00b0C). Moreover, HSA selectively blocks, in a dose dependent manner, the cytotoxic activity of ruxolitinib in JAK2V617F<jats:sup>+<\/jats:sup>\u2009cellular models for MPN, <jats:italic>in vitro<\/jats:italic>. Furthermore this event is accompanied by changes in the cell cycle, p27<jats:sup>Kip1<\/jats:sup> and cyclin D3 levels, and JAK\/STAT signaling. Given the high plasma concentration of HSA, ruxolitinib trapping may be relevant <jats:italic>in vivo<\/jats:italic>.<\/jats:p>","DOI":"10.1038\/s41598-019-52852-9","type":"journal-article","created":{"date-parts":[[2019,11,8]],"date-time":"2019-11-08T14:48:06Z","timestamp":1573224486000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Ruxolitinib binding to human serum albumin: bioinformatics, biochemical and functional characterization in JAK2V617F+ cell models"],"prefix":"10.1038","volume":"9","author":[{"given":"Elisabetta","family":"De Marinis","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessia","family":"Ceccherelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberto","family":"Quattrocchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Loris","family":"Leboffe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabio","family":"Polticelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clara","family":"Nervi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paolo","family":"Ascenzi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,11,8]]},"reference":[{"key":"52852_CR1","doi-asserted-by":"publisher","first-page":"2168","DOI":"10.1056\/NEJMra1406186","volume":"376","author":"JL Spivak","year":"2017","unstructured":"Spivak, J. L. Myeloproliferative Neoplasms. N Engl J Med 376, 2168\u20132181, https:\/\/doi.org\/10.1056\/NEJMra1406186 (2017).","journal-title":"N Engl J Med"},{"key":"52852_CR2","doi-asserted-by":"publisher","first-page":"2601","DOI":"10.1038\/onc.2012.347","volume":"32","author":"W Vainchenker","year":"2013","unstructured":"Vainchenker, W. & Constantinescu, S. N. JAK\/STAT signaling in hematological malignancies. Oncogene 32, 2601\u20132613, https:\/\/doi.org\/10.1038\/onc.2012.347 (2013).","journal-title":"Oncogene"},{"key":"52852_CR3","doi-asserted-by":"publisher","first-page":"2853","DOI":"10.1038\/leu.2017.158","volume":"31","author":"E Leroy","year":"2017","unstructured":"Leroy, E. & Constantinescu, S. N. Rethinking JAK2 inhibition: towards novel strategies of more specific and versatile Janus kinase inhibition. Leukemia 31, 2853, https:\/\/doi.org\/10.1038\/leu.2017.158 (2017).","journal-title":"Leukemia"},{"key":"52852_CR4","doi-asserted-by":"publisher","first-page":"1144","DOI":"10.1038\/nature03546","volume":"434","author":"C James","year":"2005","unstructured":"James, C. et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434, 1144\u20131148, https:\/\/doi.org\/10.1038\/nature03546 (2005).","journal-title":"Nature"},{"key":"52852_CR5","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/j.blre.2014.06.002","volume":"28","author":"JO Mascarenhas","year":"2014","unstructured":"Mascarenhas, J. O., Cross, N. C. & Mesa, R. A. The future of JAK inhibition in myelofibrosis and beyond. Blood Rev 28, 189\u2013196, https:\/\/doi.org\/10.1016\/j.blre.2014.06.002 (2014).","journal-title":"Blood Rev"},{"key":"52852_CR6","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1182\/blood-2017-04-742288","volume":"130","author":"P Bose","year":"2017","unstructured":"Bose, P. & Verstovsek, S. JAK2 inhibitors for myeloproliferative neoplasms: what is next? Blood 130, 115\u2013125, https:\/\/doi.org\/10.1182\/blood-2017-04-742288 (2017).","journal-title":"Blood"},{"key":"52852_CR7","doi-asserted-by":"publisher","first-page":"82","DOI":"10.12688\/f1000research.13167.1","volume":"7","author":"W Vainchenker","year":"2018","unstructured":"Vainchenker, W. et al. JAK inhibitors for the treatment of myeloproliferative neoplasms and other disorders. F1000Res 7, 82, https:\/\/doi.org\/10.12688\/f1000research.13167.1 (2018).","journal-title":"F1000Res"},{"key":"52852_CR8","doi-asserted-by":"publisher","first-page":"3109","DOI":"10.1182\/blood-2009-04-214957","volume":"115","author":"A Quintas-Cardama","year":"2010","unstructured":"Quintas-Cardama, A. et al. Preclinical characterization of the selective JAK1\/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood 115, 3109\u20133117, https:\/\/doi.org\/10.1182\/blood-2009-04-214957 (2010).","journal-title":"Blood"},{"key":"52852_CR9","doi-asserted-by":"publisher","first-page":"2426","DOI":"10.1182\/blood-2018-01-791491","volume":"131","author":"F Passamonti","year":"2018","unstructured":"Passamonti, F. & Maffioli, M. The role of JAK2 inhibitors in MPNs 7 years after approval. Blood 131, 2426\u20132435, https:\/\/doi.org\/10.1182\/blood-2018-01-791491 (2018).","journal-title":"Blood"},{"key":"52852_CR10","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1056\/NEJMoa1110556","volume":"366","author":"C Harrison","year":"2012","unstructured":"Harrison, C. et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 366, 787\u2013798, https:\/\/doi.org\/10.1056\/NEJMoa1110556 (2012).","journal-title":"N Engl J Med"},{"key":"52852_CR11","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1056\/NEJMoa1110557","volume":"366","author":"S Verstovsek","year":"2012","unstructured":"Verstovsek, S. et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 366, 799\u2013807, https:\/\/doi.org\/10.1056\/NEJMoa1110557 (2012).","journal-title":"N Engl J Med"},{"key":"52852_CR12","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1186\/s13045-017-0527-7","volume":"10","author":"S Verstovsek","year":"2017","unstructured":"Verstovsek, S. et al. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. J Hematol Oncol 10, 156, https:\/\/doi.org\/10.1186\/s13045-017-0527-7 (2017).","journal-title":"J Hematol Oncol"},{"key":"52852_CR13","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1056\/NEJMoa1409002","volume":"372","author":"AM Vannucchi","year":"2015","unstructured":"Vannucchi, A. M. et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med 372, 426\u2013435, https:\/\/doi.org\/10.1056\/NEJMoa1409002 (2015).","journal-title":"N Engl J Med"},{"key":"52852_CR14","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/j.mam.2011.12.002","volume":"33","author":"G Fanali","year":"2012","unstructured":"Fanali, G. et al. Human serum albumin: from bench to bedside. Mol Aspects Med 33, 209\u2013290, https:\/\/doi.org\/10.1016\/j.mam.2011.12.002 (2012).","journal-title":"Mol Aspects Med"},{"key":"52852_CR15","doi-asserted-by":"publisher","first-page":"1117","DOI":"10.1056\/NEJMoa1002028","volume":"363","author":"S Verstovsek","year":"2010","unstructured":"Verstovsek, S. et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med 363, 1117\u20131127, https:\/\/doi.org\/10.1056\/NEJMoa1002028 (2010).","journal-title":"N Engl J Med"},{"key":"52852_CR16","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1016\/j.clml.2014.12.008","volume":"15","author":"RA Mesa","year":"2015","unstructured":"Mesa, R. A. et al. Effects of Ruxolitinib Treatment on Metabolic and Nutritional Parameters in Patients With Myelofibrosis From COMFORT-I. Clinical Lymphoma Myeloma & Leukemia 15, 214\u2013221, https:\/\/doi.org\/10.1016\/j.clml.2014.12.008 (2015).","journal-title":"Clinical Lymphoma Myeloma & Leukemia"},{"key":"52852_CR17","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.bcmd.2018.06.001","volume":"72","author":"M Lucijanic","year":"2018","unstructured":"Lucijanic, M. et al. Combining information on C reactive protein and serum albumin into the Glasgow Prognostic Score strongly discriminates survival of myelofibrosis patients. Blood Cells Molecules and Diseases 72, 14\u201316, https:\/\/doi.org\/10.1016\/j.bcmd.2018.06.001 (2018).","journal-title":"Blood Cells Molecules and Diseases"},{"key":"52852_CR18","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1007\/s00508-018-1318-z","volume":"130","author":"M Lucijanic","year":"2018","unstructured":"Lucijanic, M. et al. Assessing serum albumin concentration, lymphocyte count and prognostic nutritional index might improve prognostication in patients with myelofibrosis. Wiener Klinische Wochenschrift 130, 126\u2013133, https:\/\/doi.org\/10.1007\/s00508-018-1318-z (2018).","journal-title":"Wiener Klinische Wochenschrift"},{"key":"52852_CR19","doi-asserted-by":"publisher","first-page":"1980","DOI":"10.1182\/bloodadvances.2018018051","volume":"2","author":"A Tefferi","year":"2018","unstructured":"Tefferi, A. et al. Development of a prognostically relevant cachexia index in primary myelofibrosis using serum albumin and cholesterol levels. Blood Adv 2, 1980\u20131984, https:\/\/doi.org\/10.1182\/bloodadvances.2018018051 (2018).","journal-title":"Blood Adv"},{"key":"52852_CR20","doi-asserted-by":"publisher","first-page":"D1074","DOI":"10.1093\/nar\/gkx1037","volume":"46","author":"DS Wishart","year":"2018","unstructured":"Wishart, D. S. et al. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res 46, D1074\u2013D1082, https:\/\/doi.org\/10.1093\/nar\/gkx1037 (2018).","journal-title":"Nucleic Acids Res"},{"key":"52852_CR21","unstructured":"PubChem. Ruxolitinib, CID 25126798, <https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/Ruxolitinib#section=Top> (2019)."},{"key":"52852_CR22","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1007\/s10953-017-0590-2","volume":"46","author":"Z Sharif-Barfeh","year":"2017","unstructured":"Sharif-Barfeh, Z. et al. Multi-spectroscopic and HPLC Studies of the Interaction Between Estradiol and Cyclophosphamide With Human Serum Albumin: Binary and Ternary Systems. Journal of Solution Chemistry 46, 488\u2013504, https:\/\/doi.org\/10.1007\/s10953-017-0590-2 (2017).","journal-title":"Journal of Solution Chemistry"},{"key":"52852_CR23","doi-asserted-by":"publisher","first-page":"1936","DOI":"10.1080\/07391102.2013.843062","volume":"32","author":"M Zolfagharzadeh","year":"2014","unstructured":"Zolfagharzadeh, M., Pirouzi, M., Asoodeh, A., Saberi, M. R. & Chamani, J. A comparison investigation of DNP-binding effects to HSA and HTF by spectroscopic and molecular modeling techniques. J Biomol Struct Dyn 32, 1936\u20131952, https:\/\/doi.org\/10.1080\/07391102.2013.843062 (2014).","journal-title":"J Biomol Struct Dyn"},{"key":"52852_CR24","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1016\/j.abb.2014.07.001","volume":"560","author":"E Di Muzio","year":"2014","unstructured":"Di Muzio, E. et al. Imatinib binding to human serum albumin modulates heme association and reactivity. Arch Biochem Biophys 560, 100\u2013112, https:\/\/doi.org\/10.1016\/j.abb.2014.07.001 (2014).","journal-title":"Arch Biochem Biophys"},{"key":"52852_CR25","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.abb.2015.10.014","volume":"590","author":"E Di Muzio","year":"2016","unstructured":"Di Muzio, E. et al. All-trans-retinoic acid and retinol binding to the FA1 site of human serum albumin competitively inhibits heme-Fe(III) association. Arch Biochem Biophys 590, 56\u201363, https:\/\/doi.org\/10.1016\/j.abb.2015.10.014 (2016).","journal-title":"Arch Biochem Biophys"},{"issue":"11","key":"52852_CR26","doi-asserted-by":"publisher","first-page":"e2641","DOI":"10.1002\/jmr.2641","volume":"30","author":"Fabio Polticelli","year":"2017","unstructured":"Polticelli, F. et al. Cantharidin inhibits competitively heme-Fe(III) binding to the FA1 site of human serum albumin. J Mol Recognit 30, https:\/\/doi.org\/10.1002\/jmr.2641 (2017).","journal-title":"Journal of Molecular Recognition"},{"key":"52852_CR27","first-page":"1052","volume":"12","author":"G Sudlow","year":"1976","unstructured":"Sudlow, G., Birkett, D. J. & Wade, D. N. Further characterization of specific drug binding sites on human serum albumin. Mol Pharmacol 12, 1052\u20131061 (1976).","journal-title":"Mol Pharmacol"},{"key":"52852_CR28","first-page":"824","volume":"11","author":"G Sudlow","year":"1975","unstructured":"Sudlow, G., Birkett, D. J. & Wade, D. N. The characterization of two specific drug binding sites on human serum albumin. Mol Pharmacol 11, 824\u2013832 (1975).","journal-title":"Mol Pharmacol"},{"key":"52852_CR29","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1080\/07391102.2011.672632","volume":"29","author":"G Fanali","year":"2012","unstructured":"Fanali, G., Ascenzi, P., Bernardi, G. & Fasano, M. Sequence analysis of serum albumins reveals the molecular evolution of ligand recognition properties. J Biomol Struct Dyn 29, 691\u2013701, https:\/\/doi.org\/10.1080\/07391102.2011.672632 (2012).","journal-title":"J Biomol Struct Dyn"},{"key":"52852_CR30","doi-asserted-by":"publisher","DOI":"10.2174\/0929867326666190320105316","author":"L Leboffe","year":"2019","unstructured":"Leboffe, L., di Masi, A., Polticelli, F., Trezza, V. & Ascenzi, P. Structural basis of drug recognition by human serum albumin. Curr Med Chem. https:\/\/doi.org\/10.2174\/0929867326666190320105316 (2019).","journal-title":"Curr Med Chem"},{"key":"52852_CR31","doi-asserted-by":"publisher","first-page":"1668","DOI":"10.1021\/mp400027q","volume":"10","author":"F Zsila","year":"2013","unstructured":"Zsila, F. & Subdomain, I. B. is the third major drug binding region of human serum albumin: toward the three-sites model. Mol Pharm 10, 1668\u20131682, https:\/\/doi.org\/10.1021\/mp400027q (2013).","journal-title":"Mol Pharm"},{"key":"52852_CR32","doi-asserted-by":"publisher","first-page":"10798","DOI":"10.1021\/jp4067108","volume":"117","author":"F Zsila","year":"2013","unstructured":"Zsila, F. Circular dichroism spectroscopic detection of ligand binding induced subdomain IB specific structural adjustment of human serum albumin. J Phys Chem B 117, 10798\u201310806, https:\/\/doi.org\/10.1021\/jp4067108 (2013).","journal-title":"J Phys Chem B"},{"key":"52852_CR33","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1016\/j.ijbiomac.2018.11.053","volume":"123","author":"G Rabbani","year":"2019","unstructured":"Rabbani, G. & Ahn, S. N. Structure, enzymatic activities, glycation and therapeutic potential of human serum albumin: A natural cargo. International Journal of Biological Macromolecules 123, 979\u2013990, https:\/\/doi.org\/10.1016\/j.ijbiomac.2018.11.053 (2019).","journal-title":"International Journal of Biological Macromolecules"},{"key":"52852_CR34","doi-asserted-by":"publisher","DOI":"10.1186\/1472-6807-3-6","volume":"3","author":"PA Zunszain","year":"2003","unstructured":"Zunszain, P. A., Ghuman, J., Komatsu, T., Tsuchida, E. & Curry, S. Crystal structural analysis of human serum albumin complexed with hemin and fatty acid. BMC Struct Biol 3, 6, https:\/\/doi.org\/10.1186\/1472-6807-3-6 (2003).","journal-title":"BMC Struct Biol"},{"key":"52852_CR35","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.jmb.2005.07.075","volume":"353","author":"J Ghuman","year":"2005","unstructured":"Ghuman, J. et al. Structural basis of the drug-binding specificity of human serum albumin. J Mol Biol 353, 38\u201352, https:\/\/doi.org\/10.1016\/j.jmb.2005.07.075 (2005).","journal-title":"J Mol Biol"},{"key":"52852_CR36","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1038\/1869","volume":"5","author":"S Curry","year":"1998","unstructured":"Curry, S., Mandelkow, H., Brick, P. & Franks, N. Crystal structure of human serum albumin complexed with fatty acid reveals an asymmetric distribution of binding sites. Nat Struct Biol 5, 827\u2013835, https:\/\/doi.org\/10.1038\/1869 (1998).","journal-title":"Nat Struct Biol"},{"key":"52852_CR37","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1007\/s10822-016-0006-1","volume":"31","author":"E Di Muzio","year":"2017","unstructured":"Di Muzio, E., Toti, D. & Polticelli, F. DockingApp: a user friendly interface for facilitated docking simulations with AutoDock Vina. J Comput Aided Mol Des 31, 213\u2013218, https:\/\/doi.org\/10.1007\/s10822-016-0006-1 (2017).","journal-title":"J Comput Aided Mol Des"},{"key":"52852_CR38","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.bbagen.2003.08.001","volume":"1623","author":"K Nakajou","year":"2003","unstructured":"Nakajou, K., Watanabe, H., Kragh-Hansen, U., Maruyama, T. & Otagiri, M. The effect of glycation on the structure, function and biological fate of human serum albumin as revealed by recombinant mutants. Biochim Biophys Acta 1623, 88\u201397, https:\/\/doi.org\/10.1016\/j.bbagen.2003.08.001 (2003).","journal-title":"Biochim Biophys Acta"},{"key":"52852_CR39","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.jsb.2010.10.004","volume":"174","author":"AJ Ryan","year":"2011","unstructured":"Ryan, A. J., Ghuman, J., Zunszain, P. A., Chung, C. W. & Curry, S. Structural basis of binding of fluorescent, site-specific dansylated amino acids to human serum albumin. J Struct Biol 174, 84\u201391, https:\/\/doi.org\/10.1016\/j.jsb.2010.10.004 (2011).","journal-title":"J Struct Biol"},{"key":"52852_CR40","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1002\/biof.1070","volume":"39","author":"G Fanali","year":"2013","unstructured":"Fanali, G., Fasano, M., Ascenzi, P., Zingg, J. M. & Azzi, A. alpha-Tocopherol binding to human serum albumin. Biofactors 39, 294\u2013303, https:\/\/doi.org\/10.1002\/biof.1070 (2013).","journal-title":"Biofactors"},{"key":"52852_CR41","first-page":"134","volume":"15","author":"P Ascenzi","year":"1987","unstructured":"Ascenzi, P., Ascenzi, M. G. & Amiconi, G. Enzyme competitive inhibition, graphical determination of Ki and presentation of data in comparative studies. Biochem Mol Biol Edu 15, 134\u2013135 (1987).","journal-title":"Biochem Mol Biol Edu"},{"key":"52852_CR42","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1038\/sj.leu.2404081","volume":"20","author":"H Quentmeier","year":"2006","unstructured":"Quentmeier, H., MacLeod, R. A., Zaborski, M. & Drexler, H. G. JAK2 V617F tyrosine kinase mutation in cell lines derived from myeloproliferative disorders. Leukemia 20, 471\u2013476, https:\/\/doi.org\/10.1038\/sj.leu.2404081 (2006).","journal-title":"Leukemia"},{"key":"52852_CR43","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1038\/leu.2014.285","volume":"29","author":"K Kollmann","year":"2015","unstructured":"Kollmann, K. et al. MARIMO cells harbor a CALR mutation but are not dependent on JAK2\/STAT5 signaling. Leukemia 29, 494\u2013497, https:\/\/doi.org\/10.1038\/leu.2014.285 (2015).","journal-title":"Leukemia"},{"key":"52852_CR44","doi-asserted-by":"publisher","first-page":"e54826","DOI":"10.1371\/journal.pone.0054826","volume":"8","author":"C Bogani","year":"2013","unstructured":"Bogani, C. et al. mTOR inhibitors alone and in combination with JAK2 inhibitors effectively inhibit cells of myeloproliferative neoplasms. PLoS One 8, e54826, https:\/\/doi.org\/10.1371\/journal.pone.0054826 (2013).","journal-title":"PLoS One"},{"key":"52852_CR45","doi-asserted-by":"publisher","first-page":"eaat3834","DOI":"10.1126\/sciadv.aat3834","volume":"4","author":"D Tvorogov","year":"2018","unstructured":"Tvorogov, D. et al. Accumulation of JAK activation loop phosphorylation is linked to type I JAK inhibitor withdrawal syndrome in myelofibrosis. Sci Adv. 4, eaat3834, https:\/\/doi.org\/10.1126\/sciadv.aat3834 (2018).","journal-title":"Sci Adv."},{"key":"52852_CR46","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1158\/2159-8290.CD-11-0324","volume":"2","author":"R Andraos","year":"2012","unstructured":"Andraos, R. et al. Modulation of activation-loop phosphorylation by JAK inhibitors is binding mode dependent. Cancer Discov 2, 512\u2013523, https:\/\/doi.org\/10.1158\/2159-8290.CD-11-0324 (2012).","journal-title":"Cancer Discov"},{"key":"52852_CR47","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1038\/nature11303","volume":"489","author":"P Koppikar","year":"2012","unstructured":"Koppikar, P. et al. Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Nature 489, 155\u2013159, https:\/\/doi.org\/10.1038\/nature11303 (2012).","journal-title":"Nature"},{"key":"52852_CR48","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1038\/leu.2011.255","volume":"26","author":"A Deshpande","year":"2012","unstructured":"Deshpande, A. et al. Kinase domain mutations confer resistance to novel inhibitors targeting JAK2V617F in myeloproliferative neoplasms. Leukemia 26, 708\u2013715, https:\/\/doi.org\/10.1038\/leu.2011.255 (2012).","journal-title":"Leukemia"},{"key":"52852_CR49","doi-asserted-by":"publisher","first-page":"845","DOI":"10.3324\/haematol.2010.036350","volume":"96","author":"T Hornakova","year":"2011","unstructured":"Hornakova, T. et al. Oncogenic JAK1 and JAK2-activating mutations resistant to ATP-competitive inhibitors. Haematologica 96, 845\u2013853, https:\/\/doi.org\/10.3324\/haematol.2010.036350 (2011).","journal-title":"Haematologica"},{"key":"52852_CR50","doi-asserted-by":"publisher","first-page":"1572","DOI":"10.1016\/j.ijbiomac.2017.04.051","volume":"105","author":"G Rabbani","year":"2017","unstructured":"Rabbani, G. et al. Binding of erucic acid with human serum albumin using a spectroscopic and molecular docking study. International Journal of Biological Macromolecules 105, 1572\u20131580, https:\/\/doi.org\/10.1016\/j.ijbiomac.2017.04.051 (2017).","journal-title":"International Journal of Biological Macromolecules"},{"key":"52852_CR51","doi-asserted-by":"publisher","first-page":"3550","DOI":"10.1182\/blood-2011-12-397554","volume":"119","author":"C Walz","year":"2012","unstructured":"Walz, C. et al. Essential role for Stat5a\/b in myeloproliferative neoplasms induced by BCR-ABL1 and JAK2(V617F) in mice. Blood 119, 3550\u20133560, https:\/\/doi.org\/10.1182\/blood-2011-12-397554 (2012).","journal-title":"Blood"},{"key":"52852_CR52","doi-asserted-by":"publisher","first-page":"271","DOI":"10.2165\/00003088-200038030-00005","volume":"38","author":"MK Grandison","year":"2000","unstructured":"Grandison, M. K. & Boudinot, F. D. Age-related changes in protein binding of drugs: implications for therapy. Clin Pharmacokinet 38, 271\u2013290, https:\/\/doi.org\/10.2165\/00003088-200038030-00005 (2000).","journal-title":"Clin Pharmacokinet"},{"key":"52852_CR53","doi-asserted-by":"publisher","first-page":"1731","DOI":"10.1016\/j.exger.2004.05.011","volume":"39","author":"K Turnheim","year":"2004","unstructured":"Turnheim, K. Drug therapy in the elderly. Exp Gerontol 39, 1731\u20131738, https:\/\/doi.org\/10.1016\/j.exger.2004.05.011 (2004).","journal-title":"Exp Gerontol"},{"key":"52852_CR54","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1016\/S0531-5565(03)00133-5","volume":"38","author":"K Turnheim","year":"2003","unstructured":"Turnheim, K. When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly. Exp Gerontol 38, 843\u2013853 (2003).","journal-title":"Exp Gerontol"},{"key":"52852_CR55","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.bpc.2010.03.001","volume":"148","author":"P Ascenzi","year":"2010","unstructured":"Ascenzi, P. & Fasano, M. Allostery in a monomeric protein: the case of human serum albumin. Biophys Chem 148, 16\u201322, https:\/\/doi.org\/10.1016\/j.bpc.2010.03.001 (2010).","journal-title":"Biophys Chem"},{"key":"52852_CR56","doi-asserted-by":"publisher","first-page":"1118","DOI":"10.1002\/iub.263","volume":"61","author":"P Ascenzi","year":"2009","unstructured":"Ascenzi, P. & Fasano, M. Serum heme-albumin: an allosteric protein. IUBMB Life 61, 1118\u20131122, https:\/\/doi.org\/10.1002\/iub.263 (2009).","journal-title":"IUBMB Life"},{"key":"52852_CR57","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/j.jconrel.2016.02.049","volume":"228","author":"A di Masi","year":"2016","unstructured":"di Masi, A., Trezza, V., Leboffe, L. & Ascenzi, P. Human plasma lipocalins and serum albumin: Plasma alternative carriers? J Control Release 228, 191\u2013205, https:\/\/doi.org\/10.1016\/j.jconrel.2016.02.049 (2016).","journal-title":"J Control Release"},{"key":"52852_CR58","doi-asserted-by":"publisher","first-page":"1656","DOI":"10.1021\/acs.molpharmaceut.6b01124","volume":"14","author":"G Rabbani","year":"2017","unstructured":"Rabbani, G. et al. Biophysical Study on the Interaction between Eperisone Hydrochloride and Human Serum Albumin Using Spectroscopic, Calorimetric, and Molecular Docking Analyses. Molecular Pharmaceutics 14, 1656\u20131665, https:\/\/doi.org\/10.1021\/acs.molpharmaceut.6b01124 (2017).","journal-title":"Molecular Pharmaceutics"},{"key":"52852_CR59","doi-asserted-by":"publisher","first-page":"1445","DOI":"10.1021\/acs.molpharmaceut.7b00976","volume":"15","author":"G Rabbani","year":"2018","unstructured":"Rabbani, G., Lee, E. J., Ahmad, K., Baig, M. H. & Choi, I. Binding of Tolperisone Hydrochloride with Human Serum Albumin: Effects on the Conformation, Thermodynamics, and Activity of HSA. Molecular Pharmaceutics 15, 1445\u20131456, https:\/\/doi.org\/10.1021\/acs.molpharmaceut.7b00976 (2018).","journal-title":"Molecular Pharmaceutics"},{"key":"52852_CR60","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1093\/protein\/12.6.439","volume":"12","author":"S Sugio","year":"1999","unstructured":"Sugio, S., Kashima, A., Mochizuki, S., Noda, M. & Kobayashi, K. Crystal structure of human serum albumin at 2.5 A resolution. Protein Eng 12, 439\u2013446 (1999).","journal-title":"Protein Eng"},{"key":"52852_CR61","doi-asserted-by":"publisher","first-page":"e106225","DOI":"10.1371\/journal.pone.0106225","volume":"9","author":"Y Duan","year":"2014","unstructured":"Duan, Y., Chen, L., Chen, Y. & Fan, X. G. c-Src binds to the cancer drug Ruxolitinib with an active conformation. PLoS One 9, e106225, https:\/\/doi.org\/10.1371\/journal.pone.0106225 (2014).","journal-title":"PLoS One"},{"key":"52852_CR62","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1002\/jcc.21334","volume":"31","author":"O Trott","year":"2010","unstructured":"Trott, O. & Olson, A. J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31, 455\u2013461, https:\/\/doi.org\/10.1002\/jcc.21334 (2010).","journal-title":"J Comput Chem"},{"key":"52852_CR63","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1080\/07391102.2018.1427629","volume":"37","author":"N Shakibapour","year":"2019","unstructured":"Shakibapour, N., Sani, F. D., Beigoli, S., Sadeghian, H. & Chamani, J. Multi-spectroscopic and molecular modeling studies to reveal the interaction between propyl acridone and calf thymus DNA in the presence of histone H1: binary and ternary approaches. Journal of Biomolecular Structure & Dynamics 37, 359\u2013371, https:\/\/doi.org\/10.1080\/07391102.2018.1427629 (2019).","journal-title":"Journal of Biomolecular Structure & Dynamics"},{"key":"52852_CR64","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1016\/j.jlumin.2018.06.083","volume":"203","author":"FD Sani","year":"2018","unstructured":"Sani, F. D. et al. Changes in binding affinity between ofloxacin and calf thymus DNA in the presence of histone H1: Spectroscopic and molecular modeling investigations. Journal of Luminescence 203, 599\u2013608, https:\/\/doi.org\/10.1016\/j.jlumin.2018.06.083 (2018).","journal-title":"Journal of Luminescence"},{"key":"52852_CR65","doi-asserted-by":"publisher","first-page":"1605","DOI":"10.1002\/jcc.20084","volume":"25","author":"EF Pettersen","year":"2004","unstructured":"Pettersen, E. F. et al. UCSF Chimera\u2013a visualization system for exploratory research and analysis. J Comput Chem 25, 1605\u20131612, https:\/\/doi.org\/10.1002\/jcc.20084 (2004).","journal-title":"J Comput Chem"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-52852-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-52852-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-52852-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T15:46:11Z","timestamp":1671291971000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-52852-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,8]]},"references-count":65,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["52852"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-52852-9","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,8]]},"assertion":[{"value":"24 July 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 October 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 November 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"16379"}}