Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Perspective

First Approval of Pacritinib as a Selective Janus Associated Kinase-2 Inhibitor for the Treatment of Patients with Myelofibrosis

Author(s): Surya K. De*

Volume 23, Issue 12, 2023

Published on: 11 April, 2023

Page: [1355 - 1360] Pages: 6

DOI: 10.2174/1871520623666230320120915

conference banner
Abstract

Myelofibrosis is one kind of bone marrow blood cancer that gives mainly bone marrow scarring. JAK families include JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2) and they control hematopoiesis and immune cell function. JAK-STAT pathways have the critical roles in the pathogenesis of a variety of autoimmune and inflammatory diseases such as myelofibrosis. The 8 JAK inhibitors are approved by the US FDA for the treatment of various diseases. Abrocitinib, baricitinib, oclacitinib, ruxolitinib, tofacitinib, upadacitinib, fedratinib, and pactrinib with their IC50 values against JAK1, JAK2, JAK3, and TYK2 are included. All approved JAK inhibitors with structural similarities and dissimilarities are summarized. The development story of pacritinib and new design route to overcome intellectual property-related issues by connecting the A ring and C ring to form the macrocyclic compounds like 16 without compromising the binding modes in the hinge region are discussed. By using the powerful ring-closing metathesis (RCM), they designed and synthesized and delivered FDA approved pacritinib. In this short perspective, the chemical structure, physicochemical properties, mechanism of action, drug-interactions, adverse events, and pharmacokinetic profile of pacritinib are summarized. Detailed step by step synthesis of pacritinib is provided. Pacritinib is an orally bioavailable and isoform selective JAK-2 inhibitor for the treatment of patients with myelofibrosis. Detailed metabolism pathway with proper explanation is discussed.

Keywords: Janus kinase, tyrosine kinase, autoimmune, myelofibrosis, inflammatory diseases, kinase-2.

« Previous Next »
Graphical Abstract

[1]
Tefferi, A. Primary myelofibrosis: 2014 update on diagnosis, risk-stratification, and management. Am. J. Hematol., 2014, 89(9), 915-925.
[http://dx.doi.org/10.1002/ajh.23703] [PMID: 25124313]
[2]
Finazzi, G.; Vannucchi, A.M.; Barbui, T. Prefibrotic myelofibrosis: Treatment algorithm 2018. Blood Cancer J., 2018, 8(11), 104.
[http://dx.doi.org/10.1038/s41408-018-0142-z] [PMID: 30405096]
[3]
Chou, J.M.; Li, C.Y.; Tefferi, A. Bone marrow immunohistochemical studies of angiogenic cytokines and their receptors in myelofibrosis with myeloid metaplasia. Leuk. Res., 2003, 27(6), 499-504.
[http://dx.doi.org/10.1016/S0145-2126(02)00268-0] [PMID: 12648509]
[4]
Stein, B.L. JAK inhibition in myelofibrosis: how to sequence treatment in this new era of multiple options. Leuk. Lymphoma, 2022, 64(2), 1-8.
[http://dx.doi.org/10.1080/10428194.2022.2136970] [PMID: 36301740]
[5]
Komrokji, R.S.; Seymour, J.F.; Roberts, A.W.; Wadleigh, M.; To, L.B.; Scherber, R.; Turba, E.; Dorr, A.; Zhu, J.; Wang, L.; Granston, T.; Campbell, M.S.; Mesa, R.A. Results of a phase 2 study of pacritinib (SB1518), a JAK2/JAK2(V617F) inhibitor, in patients with myelofibrosis. Blood, 2015, 125(17), 2649-2655.
[http://dx.doi.org/10.1182/blood-2013-02-484832] [PMID: 25762180]
[6]
Mesa, R.A.; Vannucchi, A.M.; Mead, A.; Egyed, M.; Szoke, A.; Suvorov, A.; Jakucs, J.; Perkins, A.; Prasad, R.; Mayer, J.; Demeter, J.; Ganly, P.; Singer, J.W.; Zhou, H.; Dean, J.P.; te Boekhorst, P.A.; Nangalia, J.; Kiladjian, J.J.; Harrison, C.N. Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial. Lancet Haematol., 2017, 4(5), e225-e236.
[http://dx.doi.org/10.1016/S2352-3026(17)30027-3] [PMID: 28336242]
[7]
Mascarenhas, J.; Hoffman, R.; Talpaz, M.; Gerds, A.T.; Stein, B.; Gupta, V.; Szoke, A.; Drummond, M.; Pristupa, A.; Granston, T.; Daly, R.; Al-Fayoumi, S.; Callahan, J.A.; Singer, J.W.; Gotlib, J.; Jamieson, C.; Harrison, C.; Mesa, R.; Verstovsek, S. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis. JAMA Oncol., 2018, 4(5), 652-659.
[http://dx.doi.org/10.1001/jamaoncol.2017.5818] [PMID: 29522138]
[8]
Salit, R.B. The role of JAK inhibitors in hematopoietic cell transplantation. Bone Marrow Transplant., 2022, 57(6), 857-865.
[http://dx.doi.org/10.1038/s41409-022-01649-y] [PMID: 35388118]
[9]
Roskoski, R. Jr Janus kinase (JAK) inhibitors in the treatment of neoplastic and inflammatory disorders. Pharmacol. Res., 2022, 183, 106362.
[http://dx.doi.org/10.1016/j.phrs.2022.106362] [PMID: 35878738]
[10]
William, A.D.; Lee, A.C.H.; Blanchard, S.; Poulsen, A.; Teo, E.L.; Nagaraj, H.; Tan, E.; Chen, D.; Williams, M.; Sun, E.T.; Goh, K.C.; Ong, W.C.; Goh, S.K.; Hart, S.; Jayaraman, R.; Pasha, M.K.; Ethirajulu, K.; Wood, J.M.; Dymock, B.W. Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetra-cyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27), 16,21,23-decaene (SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma. J. Med. Chem., 2011, 54(13), 4638-4658.
[http://dx.doi.org/10.1021/jm200326p] [PMID: 21604762]
[11]
Vazquez, M.L.; Kaila, N.; Strohbach, J.W.; Trzupek, J.D.; Brown, M.F.; Flanagan, M.E.; Mitton-Fry, M.J.; Johnson, T.A.; TenBrink, R.E.; Arnold, E.P.; Basak, A.; Heasley, S.E.; Kwon, S.; Langille, J.; Parikh, M.D.; Griffin, S.H.; Casavant, J.M.; Duclos, B.A.; Fenwick, A.E.; Harris, T.M.; Han, S.; Caspers, N.; Dowty, M.E.; Yang, X.; Banker, M.E.; Hegen, M.; Symanowicz, P.T.; Li, L.; Wang, L.; Lin, T.H.; Jussif, J.; Clark, J.D.; Telliez, J.B.; Robinson, R.P.; Unwalla, R. Identification of N-cis -3-[Methyl(7 H -pyrrolo[2,3- d]pyrimidin-4-yl)amino]cyclobutylpropane-1-sulfonamide (PF-04965842): A selective JAK1 clinical candidate for the treatment of autoimmune diseases. J. Med. Chem., 2018, 61(3), 1130-1152.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01598] [PMID: 29298069]
[12]
Davis, R.R.; Li, B.; Yun, S.Y.; Chan, A.; Nareddy, P.; Gunawan, S.; Ayaz, M.; Lawrence, H.R.; Reuther, G.W.; Lawrence, N.J.; Schönbrunn, E. Structural insights into JAK2 inhibition by ruxolitinib, fedratinib, and derivatives thereof. J. Med. Chem., 2021, 64(4), 2228-2241.
[http://dx.doi.org/10.1021/acs.jmedchem.0c01952] [PMID: 33570945]
[13]
Harrison, C.; Kiladjian, J.J.; Al-Ali, H.K.; Gisslinger, H.; Waltzman, R.; Stalbovskaya, V.; McQuitty, M.; Hunter, D.S.; Levy, R.; Knoops, L.; Cervantes, F.; Vannucchi, A.M.; Barbui, T.; Barosi, G. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N. Engl. J. Med., 2012, 366(9), 787-798.
[http://dx.doi.org/10.1056/NEJMoa1110556] [PMID: 22375970]
[14]
Williams, N.K.; Bamert, R.S.; Patel, O.; Wang, C.; Walden, P.M.; Wilks, A.F.; Fantino, E.; Rossjohn, J.; Lucet, I.S. Dissecting specificity in the Janus kinases: The structures of JAK-specific inhibitors complexed to the JAK1 and JAK2 protein tyrosine kinase domains. J. Mol. Biol., 2009, 387(1), 219-232.
[http://dx.doi.org/10.1016/j.jmb.2009.01.041] [PMID: 19361440]
[15]
Rubbert-Roth, A.; Enejosa, J.; Pangan, A.L.; Haraoui, B.; Rischmueller, M.; Khan, N.; Zhang, Y.; Martin, N.; Xavier, R.M. Trial of upadacitinib or abatacept in rheumatoid arthritis. N. Engl. J. Med., 2020, 383(16), 1511-1521.
[http://dx.doi.org/10.1056/NEJMoa2008250] [PMID: 33053283]
[16]
Levine, R.L.; Wadleigh, M.; Cools, J.; Ebert, B.L.; Wernig, G.; Huntly, B.J.P.; Boggon, T.J.; Wlodarska, I.; Clark, J.J.; Moore, S.; Adelsperger, J.; Koo, S.; Lee, J.C.; Gabriel, S.; Mercher, T.; D’Andrea, A.; Fröhling, S.; Döhner, K.; Marynen, P.; Vandenberghe, P.; Mesa, R.A.; Tefferi, A.; Griffin, J.D.; Eck, M.J.; Sellers, W.R.; Meyerson, M.; Golub, T.R.; Lee, S.J.; Gilliland, D.G. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell, 2005, 7(4), 387-397.
[http://dx.doi.org/10.1016/j.ccr.2005.03.023] [PMID: 15837627]
[17]
Baxter, E.J.; Scott, L.M.; Campbell, P.J.; East, C.; Fourouclas, N.; Swanton, S.; Vassiliou, G.S.; Bench, A.J.; Boyd, E.M.; Curtin, N.; Scott, M.A.; Erber, W.N.; Green, A.R. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet, 2005, 365(9464), 1054-1061.
[http://dx.doi.org/10.1016/S0140-6736(05)71142-9] [PMID: 15781101]
[18]
James, C.; Ugo, V.; Le Couédic, J.P.; Staerk, J.; Delhommeau, F.; Lacout, C.; Garçon, L.; Raslova, H.; Berger, R.; Bennaceur-Griscelli, A.; Villeval, J.L.; Constantinescu, S.N.; Casadevall, N.; Vainchenker, W. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature, 2005, 434(7037), 1144-1148.
[http://dx.doi.org/10.1038/nature03546] [PMID: 15793561]
[19]
Blanchard, S.; Lee, C.H.A.; Nagaraj, H.K.M.; Poulsen, A.; Sun, E.T.; Tan, Y.L.E.; William, A.D. Oxygen linked pyrimidine derivatives. US8415338B2, 2013.
[20]
Jayaraman, R.; Pasha, M.; Williams, A.; Goh, K.; Ethirajulu, K. Metabolism and disposition of pacritinib (SB1518), an orally active janus kinase 2 inhibitor in preclinical species and humans. Drug Metab. Lett., 2015, 9(1), 28-47.
[http://dx.doi.org/10.2174/1872312809666150119105250] [PMID: 25600203]
[21]
Shawky, A.M.; Almalki, F.A.; Abdalla, A.N.; Abdelazeem, A.H.; Gouda, A.M. A comprehensive overview of globally approved JAK inhibitors. Pharmaceutics, 2022, 14(5), 1001.
[http://dx.doi.org/10.3390/pharmaceutics14051001] [PMID: 35631587]
[22]
Cafardi, J.; Miller, C.; Terebelo, H.; Tewell, C.; Benzaquen, S.; Park, D.; Egan, P.; Lebovic, D.; Pettit, K.; Whitman, E.; Tremblay, D.; Feld, J.; Buckley, S.; Roman-Torres, K.; Smith, J.; Craig, A.; Mascarenhas, J. Efficacy and safety of pacritinib vs placebo for patients with severe COVID-19. JAMA Netw. Open, 2022, 5(12), e2242918.
[http://dx.doi.org/10.1001/jamanetworkopen.2022.42918] [PMID: 36469321]

Rights & Permissions Print Cite
Article Metrics
70
2
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy