Abstract
Bruton’s tyrosine kinase (BTK) kinase is a member of the TEC kinase family and is a key regulator of the B-cell receptor (BCR)-mediated signaling pathway. It is important for B-cell maturation, proliferation, survival and metastasis. Pharmacological inhibition of BTK is clinically effective against a variety of B-cell malignances, such as mantle cell lymphoma, chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML) and activated B-cell–diffuse large B-cell lymphoma. MNK kinase is one of the key downstream regulators in the RAF–MEK–ERK signaling pathway and controls protein synthesis via regulating the activity of eIF4E. Inhibition of MNK activity has been observed to moderately inhibit the proliferation of AML cells. Through a structure-based drug-design approach, we have discovered a selective and potent BTK/MNK dual kinase inhibitor (QL-X-138), which exhibits covalent binding to BTK and noncovalent binding to MNK. Compared with the BTK kinase inhibitor (PCI-32765) and the MNK kinase inhibitor (cercosporamide), QL-X-138 enhanced the antiproliferative efficacies in vitro against a variety of B-cell cancer cell lines, as well as AML and CLL primary patient cells, which respond moderately to BTK inhibitor in vitro. The agent can effectively arrest the growth of lymphoma and leukemia cells at the G0–G1 stage and can induce strong apoptotic cell death. These primary results demonstrate that simultaneous inhibition of BTK and MNK kinase activity might be a new therapeutic strategy for B-cell malignances.
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References
Vetrie D, Vorechovsky I, Sideras P, Holland J, Davies A, Flinter F et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature 1993; 361: 226–233.
Tsukada S, Saffran DC, Rawlings DJ, Parolini O, Allen RC, Klisak I et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell 1993; 72: 279–290.
Wiestner A . Targeting B-Cell receptor signaling for anticancer therapy: the Bruton's tyrosine kinase inhibitor ibrutinib induces impressive responses in B-cell malignancies. J Clin Oncol 2013; 31: 128–130.
Hendriks RW, Yuvaraj S, Kil LP . Targeting Bruton's tyrosine kinase in B cell malignancies. Nat Rev Cancer 2014; 14: 219–232.
Aoki Y, Isselbacher KJ, Pillai S . Bruton tyrosine kinase is tyrosine phosphorylated and activated in pre-B lymphocytes and receptor-ligated B cells. Proc Natl Acad Sci USA 1994; 91: 10606–10609.
Kurosaki T, Tsukada S . BLNK: connecting Syk and Btk to calcium signals. Immunity 2000; 12: 1–5.
Schwartzberg PL, Finkelstein LD, Readinger JA . TEC-family kinases: regulators of T-helper-cell differentiation. Nat Rev Immunol 2005; 5: 284–295.
D'Cruz OJ, Uckun FM . Novel Bruton's tyrosine kinase inhibitors currently in development. Onco Targets Ther 2013; 6: 161–176.
Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013; 369: 32–42.
Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2013; 369: 507–516.
Woyach JA, Bojnik E, Ruppert AS, Stefanovski MR, Goettl VM, Smucker KA et al. Bruton's tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL). Blood 2014; 123: 1207–1213.
Akinleye A, Chen Y, Mukhi N, Song Y, Liu D . Ibrutinib and novel BTK inhibitors in clinical development. J Hematol Oncol 2013; 6: 59.
Rushworth SA, Murray MY, Zaitseva L, Bowles KM, MacEwan DJ . Identification of Bruton's tyrosine kinase as a therapeutic target in acute myeloid leukemia. Blood 2014; 123: 1229–1238.
Diab S, Kumarasiri M, Yu M, Teo T, Proud C, Milne R et al. MAP kinase-interacting kinases-emerging targets against cancer. Chem Biol 2014; 21: 441–452.
Lazaris-Karatzas A, Montine KS, Sonenberg N . Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5' cap. Nature 1990; 345: 544–547.
Mamane Y, Petroulakis E, Martineau Y, Sato TA, Larsson O, Rajasekhar VK et al. Epigenetic activation of a subset of mRNAs by eIF4E explains its effects on cell proliferation. PLoS One 2007; 2: e242.
Graff JR, Konicek BW, Carter JH, Marcusson EG . Targeting the eukaryotic translation initiation factor 4E for cancer therapy. Cancer Res 2008; 68: 631–634.
Ruggero D, Montanaro L, Ma L, Xu W, Londei P, Cordon-Cardo C et al. The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis. Nat Med 2004; 10: 484–486.
Hou J, Lam F, Proud C, Wang S . Targeting Mnks for cancer therapy. Oncotarget 2012; 3: 118–131.
Konicek BW, Stephens JR, McNulty AM, Robichaud N, Peery RB, Dumstorf CA et al. Therapeutic inhibition of MAP kinase interacting kinase blocks eukaryotic initiation factor 4E phosphorylation and suppresses outgrowth of experimental lung metastases. Cancer Res 2011; 71: 1849–1857.
Altman JK, Szilard A, Konicek BW, Iversen PW, Kroczynska B, Glaser H et al. Inhibition of Mnk kinase activity by cercosporamide and suppressive effects on acute myeloid leukemia precursors. Blood 2013; 121: 3675–3681.
Dasmahapatra G, Patel H, Dent P, Fisher RI, Friedberg J, Grant S . The Bruton tyrosine kinase (BTK) inhibitor PCI-32765 synergistically increases proteasome inhibitor activity in diffuse large-B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells sensitive or resistant to bortezomib. Br J Haematol 2013; 161: 43–56.
Zhang M, Fu W, Prabhu S, Moore JC, Ko J, Kim JW et al. Inhibition of polysome assembly enhances imatinib activity against chronic myelogenous leukemia and overcomes imatinib resistance. Mol Cell Biol 2008; 28: 6496–6509.
Zhou W, Ercan D, Chen L, Yun CH, Li D, Capelletti M et al. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature 2009; 462: 1070–1074.
Minor W, Cymborowski M, Otwinowski Z, Chruszcz M . HKL-3000: the integration of data reduction and structure solution—from diffraction images to an initial model in minutes. Acta Crystallogr D Biol Crystallogr 2006; 62: 859–866.
Adams PD, Afonine PV, Bunkoczi G, Chen VB, Davis IW, Echols N et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr D Biol Crystallogr 2010; 66: 213–221.
Emsley P, Lohkamp B, Scott WG, Cowtan K . Features and development of Coot. Acta Crystallogr D Biol Crystallogr 2010; 66: 486–501.
Schuttelkopf AW, van Aalten DM . PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr D Biol Crystallogr 2004; 60: 1355–1363.
Pan Z, Scheerens H, Li SJ, Schultz BE, Sprengeler PA, Burrill LC et al. Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase. Chem Med Chem 2007; 2: 58–61.
Evans EK, Tester R, Aslanian S, Karp R, Sheets M, Labenski MT et al. Inhibition of Btk with CC-292 provides early pharmacodynamic assessment of activity in mice and humans. J Pharmacol Exp Ther 2013; 346: 219–228.
Jauch R, Jakel S, Netter C, Schreiter K, Aicher B, Jackle H et al. Crystal structures of the Mnk2 kinase domain reveal an inhibitory conformation and a zinc binding site. Structure 2005; 13: 1559–1568.
Liu Q, Wang J, Kang SA, Thoreen CC, Hur W, Ahmed T et al. Discovery of 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective, and orally available mammalian target of rapamycin (mTOR) inhibitor for treatment of cancer. J Med Chem 2011; 54: 1473–1480.
Fabian MA, Biggs WH 3rd, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG et al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 2005; 23: 329–336.
Honigberg LA, Smith AM, Sirisawad M, Verner E, Loury D, Chang B et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci USA 2010; 107: 13075–13080.
Liu F, Zhang X, Weisberg E, Chen S, Hur W, Wu H et al. Discovery of a selective irreversible BMX inhibitor for prostate cancer. ACS Chem Biol 2013; 8: 1423–1428.
Cope CL, Gilley R, Balmanno K, Sale MJ, Howarth KD, Hampson M et al. Adaptation to mTOR kinase inhibitors by amplification of eIF4E to maintain cap-dependent translation. J Cell Sci 2014; 127: 788–800.
Stead RL, Proud CG . Rapamycin enhances eIF4E phosphorylation by activating MAP kinase-interacting kinase 2a (Mnk2a). FEBS Lett 2013; 587: 2623–2628.
Axelrod M, Ou Z, Brett LK, Zhang L, Lopez ER, Tamayo AT et al. Combinatorial drug screening identifies synergistic co-targeting of Bruton's tyrosine kinase and the proteasome in mantle cell lymphoma. Leukemia 2014; 28: 407–410.
Kummar S, Chen HX, Wright J, Holbeck S, Millin MD, Tomaszewski J et al. Utilizing targeted cancer therapeutic agents in combination: novel approaches and urgent requirements. Nat Rev Drug Discov 2010; 9: 843–856.
Morphy R, Kay C, Rankovic Z . From magic bullets to designed multiple ligands. Drug Discov Today 2004; 9: 641–651.
Schrattenholz A, Soskic V . What does systems biology mean for drug development? Curr Med Chem 2008; 15: 1520–1528.
Hopkins AL . Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol 2008; 4: 682–690.
Acknowledgements
WW, JL and QL are supported by the grant of ‘Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation (2014–2016)’ from Chinese Academy of Sciences. ZZ is supported by Anhui Province Natural Science Foundation Annual Key Program (grant number: 1301023011). We thank China ‘Thousand Talents Program’ support for QL and ‘Hundred Talents Program’ of The Chinese Academy of Sciences support for JL and WW. We thank Scientific Research Grant of Hefei Science Center of CAS (SRG-HSC # 2015SRG-HSC022) for supporting of QL.
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Wu, H., Hu, C., Wang, A. et al. Discovery of a BTK/MNK dual inhibitor for lymphoma and leukemia. Leukemia 30, 173–181 (2016). https://doi.org/10.1038/leu.2015.180
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DOI: https://doi.org/10.1038/leu.2015.180
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