Abstract
Background: Aberrant and proliferative expression of the oncogene BCR-ABL in bone marrow cells is one of the prime causes of Chronic Myeloid Leukemia (CML). It has been established that the tyrosine kinase domain of the BCR-ABL protein is a potential therapeutic target for the treatment of CML. Although the first and second line inhibitors against the enzyme are available, recent studies have indicated that monotherapeutic resistance has become a great challenge.
Objective: In recent studies, the dual inhibition of BCR-ABL by Nilotinib and Asciminib has been shown to overcome drug resistance. This prompted us to investigate the dynamics behind this novel drug combination.
Methods: By the utilization of a wide range of computational tools, we defined and compared BCR-ABL’s structural and dynamic characteristics when bound as a dual inhibitor system.
Results: Conformational ensemble analysis presented a sustained inactive protein, as the activation loop, inclusive of the characteristic Tyr257, remained in an open position due to the unassailable binding of Asciminib at the allosteric site. Nilotinib also indicated stronger binding at the catalytic site in the presence of Asciminib, thus exposing new avenues in treating Nilotinib-resistance. This was in accordance with intermolecular hydrogen bond interactions with key binding site residues GLU399, Asn259 and Thr252.
Conclusion: The investigations carried out in this study gave rise to new possibilities in the treatment of resistance in CML, as well as assisting in the design of novel and selective inhibitors as dual anti-cancer drugs.
Keywords: Dual inhibition, CML therapy, anti-cancer drugs, allosteric inhibition, synergistic duality, BCR-ABL1.
Graphical Abstract
[1]
Deininger, M.W. Diagnosing and managing advanced chronic myeloid leukemia. Am. Soc. Clin. Oncol. Educ. Book, 2015, 35, e381-e388.
[2]
Granatowicz, A.; Piatek, C.I.; Moschiano, E.; El-Hemaidi, I.; Armitage, J.D.; Akhtari, M. An overview and update of chronic myeloid leukemia for primary care physicians. Korean J. Fam. Med., 2015, 36(5), 197-202.
[3]
Baccarani, M.; Pileri, S.; Steegmann, J-L.; Muller, M.; Soverini, S.; Dreyling, M. Chronic myeloid leukemia: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol., 2012, 23(Suppl. 7), vii72-vii77.
[4]
Matutes, E.; Pickl, W.F.; Van’t Veer, M.; Morilla, R.; Swansbury, J.; Strobl, H.; Attarbaschi, A.; Hopfinger, G.; Ashley, S.; Bene, M.C.; Porwit, A.; Orfao, A.; Lemez, P.; Schabath, R.; Ludwig, W.D. Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification. Blood, 2011, 117(11), 3163-3171.
[5]
Clark, S.S.; McLaughlin, J.; Timmons, M.; Pendergast, A.M.; Ben-Neriah, Y.; Dow, L.W.; Crist, W.; Rovera, G.; Smith, S.D.; Witte, O.N. Expression of a distinctive BCR-ABL oncogene in Ph1-positive acute lymphocytic leukemia (ALL). Science, 1988, 239(4841 Pt 1), 775-777.
[6]
Konopka, J.B.; Watanabe, S.M.; Witte, O.N. An alteration of the human c-abl protein in K562 leukemia cells unmasks associated tyrosine kinase activity. Cell, 1984, 37(3), 1035-1042.
[8]
Liu, J.; Campbell, M.; Guo, J.Q.; Lu, D.; Xian, Y.M.; Andersson, B.S.; Arlinghaus, R.B. BCR-ABL tyrosine kinase is autophosphorylated or transphosphorylates P160 BCR on tyrosine predominantly within the first BCR exon. Oncogene, 1993, 8(1), 101-109.
[9]
Pendergast, A.M.; Quilliam, L.A.; Cripe, L.D.; Bassing, C.H.; Dai, Z.; Li, N.; Batzer, A.; Rabun, K.M.; Der, C.J.; Schlessinger, J. BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Cell, 1993, 75(1), 175-185.
[10]
Ben-Neriah, Y.; Daley, G.Q.; Mes-Masson, A.M.; Witte, O.N.; Baltimore, D. The chronic myelogenous leukemia-specific P210 protein is the product of the bcr/abl hybrid gene. Science, 1986, 233(4760), 212-214.
[11]
Yang, J.; Campobasso, N.; Biju, M.P.; Fisher, K.; Pan, X-Q.; Cottom, J.; Galbraith, S.; Ho, T.; Zhang, H.; Hong, X.; Ward, P.; Hofmann, G.; Siegfried, B.; Zappacosta, F.; Washio, Y.; Cao, P.; Qu, J.; Bertrand, S.; Wang, D.Y.; Head, M.S.; Li, H.; Moores, S.; Lai, Z.; Johanson, K.; Burton, G.; Erickson-Miller, C.; Simpson, G.; Tummino, P.; Copeland, R.A.; Oliff, A. Discovery and characterization of a cell-permeable, small-molecule c-Abl kinase activator that binds to the myristoyl binding site. Chem. Biol., 2011, 18(2), 177-186.
[12]
Nagar, B.; Hantschel, O.; Young, M.A.; Scheffzek, K.; Veach, D.; Bornmann, W.; Clarkson, B.; Superti-Furga, G.; Kuriyan, J. Structural basis for the autoinhibition of c-Abl tyrosine kinase. Cell, 2003, 112(6), 859-871.
[13]
Wylie, A.; Schoepfer, J.; Berellini, G.; Cai, H.; Caravatti, G.; Cotesta, S.; Dodd, S.; Donovan, D.; Erb, B.; Furet, P.; Gangal, G.; Grotzfeld, R.; Hassan, Q.; Hood, T.; Iyer, I.; Jacob, S.; Ja, W. ABL001, a potent allosteric inhibitor of BCR-ABL, prevents emergence of resistant disease when administered in combination with nilotinib in an in vivo murine model of chronic myeloid leukemia. Blood, 2014, 124, 398-398.
[14]
Eadie, L.N.; Saunders, V.A.; Leclercq, T.M.; Branford, S.; White, D.L.; Hughes, T.P. The allosteric inhibitor ABL001 is susceptible to resistance in vitro mediated by overexpression of the drug efflux transporters ABCB1 and ABCG2. Blood, 2015, 126(23), 4841-4841.
[15]
Wylie, A.A.; Schoepfer, J.; Jahnke, W.; Cowan-Jacob, S.W.; Loo, A.; Furet, P.; Marzinzik, A.L.; Pelle, X.; Donovan, J.; Zhu, W.; Buonamici, S.; Hassan, A.Q.; Lombardo, F.; Iyer, V.; Palmer, M.; Berellini, G.; Dodd, S.; Thohan, S.; Bitter, H.; Branford, S.; Ross, D.M.; Hughes, T.P.; Petruzzelli, L.; Vanasse, K.G.; Warmuth, M.; Hofmann, F.; Keen, N.J.; Sellers, W.R. The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Nature, 2017, 543(7647), 733-737.
[16]
Ottmann, O.G.; Alimena, G.; DeAngelo, D.J.; Goh, Y-T.; Heinrich, M.C.; Hochhaus, A.; Hughes, T.P.; Mahon, F-X.; Mauro, M.J.; Minami, H. ABL001, a Potent, allosteric inhibitor of BCR-ABL, exhibits safety and promising single- agent activity in a phase i study of patients with CML with failure of prior TKI therapy. Blood, 2015, 126(23), 138-138.
[17]
Hughes, T.P.; Goh, Y-T.; Ottmann, O.G.; Minami, H.; Rea, D.; Lang, F.; Mauro, M.J.; DeAngelo, D.J.; Talpaz, M.; Hochhaus, A. Expanded phase 1 study of ABL001, a Potent, allosteric inhibitor of BCR-ABL, reveals significant and durable responses in patients with CML-chronic phase with failure of prior TKI therapy. Blood, 2016, 128(22), 625-625.
[18]
Druker, B.J.; Sawyers, C.L.; Kantarjian, H.; Resta, D.J.; Reese, S.F.; Ford, J.M.; Capdeville, R.; Talpaz, M. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N. Engl. J. Med., 2001, 344(14), 1038-1042.
[19]
Hassan, A.Q.; Sharma, S.V.; Warmuth, M. Allosteric inhibition of BCR-ABL. Cell Cycle, 2010, 9(18), 3710-3714.
[20]
Giles, F.J.; le Coutre, P.D.; Pinilla-Ibarz, J.; Larson, R.A.; Gattermann, N.; Ottmann, O.G.; Hochhaus, A.; Radich, J.P.; Saglio, G.; Hughes, T.P.; Martinelli, G.; Kim, D.W.; Novick, S.; Gillis, K.; Fan, X.; Cortes, J.; Baccarani, M.; Kantarjian, H.M. Nilotinib in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase II study. Leukemia, 2013, 27(1), 107-112.
[21]
Rogers, G.; Hoyle, M.; Thompson Coon, J.; Moxham, T.; Liu, Z.; Pitt, M.; Stein, K. Dasatinib and nilotinib for imatinib-resistant or -intolerant chronic myeloid leukaemia: A systematic review and economic evaluation. Health Technol. Assess., 2012, 16(22), 1-410.
[22]
Jarkowski, A.; Sweeney, R.P. Nilotinib: A new tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia. Pharmacotherapy, 2008, 28(11), 1374-1382.
[23]
Blay, J.Y.; von Mehren, M. Nilotinib: A novel, selective tyrosine kinase inhibitor. Semin. Oncol., 2011, 3(Suppl. 1), S3-S9.
[24]
Bleeker, F.E.; Bardelli, A. Genomic landscapes of cancers: Prospects for targeted therapies. Pharmacogenomics, 2007, 8(12), 1629-1633.
[25]
Cowan-Jacob, S.W. The role of structure and biophysics in the discovery of allosteric kinase inhibitors: ABL001, a potent and specific inhibitor of BCR-ABL. Acta Crystallogr., 2016, 72(a1), s4-s5.
[26]
Schoepfer, J.; Jahnke, W.; Berellini, G.; Buonamici, S.; Cotesta, S.; Cowan-Jacob, S.W.; Dodd, S.; Drueckes, P.; Fabbro, D.; Gabriel, T.; Groell, J.M.; Grotzfeld, R.M.; Hassan, A.Q.; Henry, C.; Iyer, V.; Jones, D.; Lombardo, F.; Loo, A.; Manley, P.W.; Pellé, X.; Rummel, G.; Salem, B.; Warmuth, M.; Wylie, A.A.; Zoller, T.; Marzinzik, A.L.; Furet, P. Discovery of Asciminib (ABL001), an allosteric inhibitor of the tyrosine kinase activity of BCR-ABL1. J. Med. Chem., 2018, 61(18), 8120-8135.
[27]
Block, K.I.; Gyllenhaal, C.; Lowe, L.; Amedei, A.; Amin, A.R.M.R.; Amin, A.; Aquilano, K.; Arbiser, J.; Arreola, A.; Arzumanyan, A.; Ashraf, S.S.; Azmi, A.S.; Benencia, F.; Bhakta, D.; Bilsland, A.; Bishayee, A.; Blain, S.W.; Block, P.B.; Boosani, C.S.; Carey, T.E.; Carnero, A.; Carotenuto, M.; Casey, S.C.; Chakrabarti, M.; Chaturvedi, R.; Chen, G.Z.; Chen, H.; Chen, S.; Chen, Y.C.; Choi, B.K.; Ciriolo, M.R.; Coley, H.M.; Collins, A.R.; Connell, M.; Crawford, S.; Curran, C.S.; Dabrosin, C.; Damia, G.; Dasgupta, S.; DeBerardinis, R.J.; Decker, W.K.; Dhawan, P.; Diehl, A.M.E.; Dong, J.T.; Dou, Q.P.; Drew, J.E.; Elkord, E.; El-Rayes, B.; Feitelson, M.A.; Felsher, D.W.; Ferguson, L.R.; Fimognari, C.; Firestone, G.L.; Frezza, C.; Fujii, H.; Fuster, M.M.; Generali, D.; Georgakilas, A.G.; Gieseler, F.; Gilbertson, M.; Green, M.F.; Grue, B.; Guha, G.; Halicka, D.; Helferich, W.G.; Heneberg, P.; Hentosh, P.; Hirschey, M.D.; Hofseth, L.J.; Holcombe, R.F.; Honoki, K.; Hsu, H.Y.; Huang, G.S.; Jensen, L.D.; Jiang, W.G.; Jones, L.W.; Karpowicz, P.A.; Keith, W.N.; Kerkar, S.P.; Khan, G.N.; Khatami, M.; Ko, Y.H.; Kucuk, O.; Kulathinal, R.J.; Kumar, N.B.; Kwon, B.S.; Le, A.; Lea, M.A.; Lee, H.Y.; Lichtor, T.; Lin, L.T.; Locasale, J.W.; Lokeshwar, B.L.; Longo, V.D.; Lyssiotis, C.A.; MacKenzie, K.L.; Malhotra, M.; Marino, M.; Martinez-Chantar, M.L.; Matheu, A.; Maxwell, C.; McDonnell, E.; Meeker, A.K.; Mehrmohamadi, M.; Mehta, K.; Michelotti, G.A.; Mohammad, R.M.; Mohammed, S.I.; Morre, D.J.; Muralidhar, V.; Muqbil, I.; Murphy, M.P.; Nagaraju, G.P.; Nahta, R.; Niccolai, E.; Nowsheen, S.; Panis, C.; Pantano, F.; Parslow, V.R.; Pawelec, G.; Pedersen, P.L.; Poore, B.; Poudyal, D.; Prakash, S.; Prince, M.; Raffaghello, L.; Rathmell, J.C.; Rathmell, W.K.; Ray, S.K.; Reichrath, J.; Rezazadeh, S.; Ribatti, D.; Ricciardiello, L.; Robey, R.B.; Rodier, F.; Rupasinghe, H.P.V.; Russo, G.L.; Ryan, E.P.; Samadi, A.K.; Sanchez-Garcia, I.; Sanders, A.J.; Santini, D.; Sarkar, M.; Sasada, T.; Saxena, N.K.; Shackelford, R.E.; Shantha Kumara, H.M.C.; Sharma, D.; Shin, D.M.; Sidransky, D.; Siegelin, M.D.; Signori, E.; Singh, N.; Sivanand, S.; Sliva, D.; Smythe, C.; Spagnuolo, C.; Stafforini, D.M.; Stagg, J.; Subbarayan, P.R.; Sundin, T.; Talib, W.H.; Thompson, S.K.; Tran, P.T.; Ungefroren, H.; Vander Heiden, M.G.; Venkateswaran, V.; Vinay, D.S.; Vlachostergios, P.J.; Wang, Z.; Wellen, K.E.; Whelan, R.L.; Yang, E.S.; Yang, H.; Yang, X.; Yaswen, P.; Yedjou, C.; Yin, X.; Zhu, J.; Zollo, M. Designing a broad-spectrum integrative approach for cancer prevention and treatment. Semin. Cancer Biol., 2015, 35(Suppl. 3), S276-S304.
[28]
Petrelli, A.; Giordano, S. From single- to multi-target drugs in cancer therapy: When aspecificity becomes an advantage. Curr. Med. Chem., 2008, 15(5), 422-432.
[29]
Berman, H.M.; Battistuz, T.; Bhat, T.N.; Bluhm, W.F.; Bourne, P.E.; Burkhardt, K.; Feng, Z.; Gilliland, G.L.; Iype, L.; Jain, S.; Fagan, P.; Marvin, J.; Padilla, D.; Ravichandran, V.; Schneider, B.; Thanki, N.; Weissig, H.; Westbrook, J.D.; Zardecki, C. The Protein Data Bank. Acta Crystallogr. D Biol. Crystallogr., 2002, 58(Pt 6 No 1), 899-907.
[30]
Kim, S.; Thiessen, P.A.; Bolton, E.E.; Chen, J.; Fu, G.; Gindulyte, A.; Han, L.; He, J.; He, S.; Shoemaker, B.A.; Wang, J.; Yu, B.; Zhang, J.; Bryant, S.H. PubChem substance and compound databases. Nucleic Acids Res., 2016, 44(D1), D1202-D1213.
[31]
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., 2010, 31(2), 455-461.
[32]
Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera--a visualization system for exploratory research and analysis. J. Comput. Chem., 2004, 25(13), 1605-1612.
[33]
Adcock, S.A.; McCammon, J.A. Molecular dynamics: Survey of methods for simulating the activity of proteins. Chem. Rev., 2006, 106(5), 1589-1615.
[34]
Case, D.A.; Cheatham, T.E., III; Darden, T.; Gohlke, H.; Luo, R.; Merz, K.M., Jr; Onufriev, A.; Simmerling, C.; Wang, B.; Woods, R.J. The Amber biomolecular simulation programs. J. Comput. Chem., 2005, 26(16), 1668-1688.
[35]
Ramharack, P.; Soliman, M.E.S. Zika virus NS5 protein potential inhibitors: An enhanced in silico approach in drug discovery. J. Biomol. Struct. Dyn., 2018, 36(5), 1118-1133.
[36]
El Rashedy, A.A.; Olotu, F.A.; Soliman, M.E.S. Dual drug targeting of mutant Bcr-Abl induces inactive conformation: New strategy for the treatment of chronic myeloid leukemia and overcoming monotherapy resistance. Chem. Biodivers., 2018, 15(3)e170053
[37]
Ramharack, P.; Oguntade, S.; Soliman, M.E.S. Delving into zika virus structural dynamics – a closer look at NS3 helicase loop flexibility and its role in drug discovery. RSC Adv, 2017, 7(36), 22133-22144.
[38]
Roe, D.R.; Cheatham, T.E. III PTRAJ and CPPTRAJ: Software for processing and analysis of molecular dynamics trajectory data. J. Chem. Theory Comput., 2013, 9(7), 3084-3095.
[39]
Ylilauri, M.; Pentikäinen, O.T. MMGBSA as a tool to understand the binding affinities of filamin-peptide interactions. J. Chem. Inf. Model., 2013, 53(10), 2626-2633.
[40]
Hou, T.; Wang, J.; Li, Y.; Wang, W. Assessing the performance of the MM/PBSA and MM/GBSA methods. The accuracy of binding free energy calculations based on molecular dynamics simulations. J. Chem. Inf. Model., 2011, 51(1), 69-82.
[41]
Hayes, J.M.; Archontis, G. MM-GB; SA calculations of protein-ligand binding free energies; InTech: PB, 2011, pp. 171-190.
[42]
Agoni, C.; Ramharack, P.; Soliman, M.E.S. Co-inhibition as a strategic therapeutic approach to overcome rifampin resistance in tuberculosis therapy: Atomistic insights. Future Med. Chem., 2018, 10(14), 1665-1675.
[43]
Eadie, L.N.; Saunders, V.A.; Branford, S.; White, D.L.; Hughes, T.P. The new allosteric inhibitor asciminib is susceptible to resistance mediated by ABCB1 and ABCG2 overexpression in vitro. Oncotarget, 2018, 9(17), 13423-13437.
[44]
Reddy, E.P.; Aggarwal, A.K. The ins and outs of BCR-ABL inhibition. Genes Cancer, 2012, 3(5-6), 447-454.
[45]
Pan, L.; Patterson, J.C.; Deshpande, A.; Cole, G.; Frautschy, S. Molecular dynamics study of Zn(aβ) and Zn(aβ)2. PLoS One, 2013, 8(9)e70681
[46]
Wijffels, G.; Dalrymple, B.; Kongsuwan, K.; Dixon, N.E. Conservation of eubacterial replicases. IUBMB Life, 2005, 57(6), 413-419.
Related Journals
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry
Current Bioactive Compounds
Current Cancer Drug Targets
Current Cancer Therapy Reviews
Current Drug Safety
Current Drug Targets
Recent Patents on Anti-Cancer Drug Discovery
Letters in Drug Design & Discovery
Current Drug Discovery Technologies
Current Radiopharmaceuticals
Related Books
Science of Spices and Culinary Herbs - Latest Laboratory, Pre-clinical, and Clinical Studies
Frontiers in Clinical Drug Research - Anti-Cancer Agents
Advances in Organic Synthesis
Frontiers in Natural Product Chemistry
Recent Advances in Analytical Techniques
Frontiers in Drug Design and Discovery
NEOPLASIA and FERTILITY
Therapeutic Use of Plant Secondary Metabolites
Frontiers in Computational Chemistry
Frontiers in Bioactive Compounds
Article Metrics
33
1