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Investigation on the interaction behavior of afatinib, dasatinib, and imatinib docked to the BCR-ABL protein

Abstract

Chronic myeloid leukemia (CML) is a pathological condition associated with the uncontrolled proliferation of white blood cells and respective loss of function. Imatinib was the first drug that could effectively treat this condition, but its use is hindered by the development of mutations of the BCR-ABL protein, which are the cause of resistance. Therefore, dasatinib and afatinib present similarities that can be explored to discover new molecules capable of overcoming the effects of imatinib. Afatinib exhibited electronic and docking behavior, indicating that a replacement with some minor modifications could design a new potential inhibitor. The amide group in each candidate is clearly of pharmacophoric importance, and it needs to concentrate a negative region. Sulfur group presents a good pharmacophoric profile, which was shown by dasatinib results, adding to the influence of the Met318 residue in the target protein active site configuration. This behavior suggests that the sulfur atom and other fragments that have an affinity for the methionine sidechain may provide a significant positive effect when present in TKI molecules such as afatinib or dasatinib.

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References

  1. Braun TP, Eide CA, Druker BJ (2020) Response and resistance to BCR-ABL1-targeted therapies. Cancer Cell 37:530–542. https://doi.org/10.1016/J.CCELL.2020.03.006

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Mosaad YM (2014) Hematopoietic stem cells: an overview. Transfus Apher Sci 51:68–82. https://doi.org/10.1016/J.TRANSCI.2014.10.016

    Article  PubMed  Google Scholar 

  3. Soverini S, Mancini M, Bavaro L et al (2018) (2018) Chronic myeloid leukemia: the paradigm of targeting oncogenic tyrosine kinase signaling and counteracting resistance for successful cancer therapy. Mol Cancer 171(17):1–15. https://doi.org/10.1186/S12943-018-0780-6

    Article  Google Scholar 

  4. Sjoberg BP, Menias CO, Lubner MG et al (2018) Splenomegaly: a combined clinical and radiologic approach to the differential diagnosis. Gastroenterol Clin North Am 47:643–666. https://doi.org/10.1016/J.GTC.2018.04.009

    Article  PubMed  Google Scholar 

  5. Hehlmann R, Saußele S, Voskanyana A, Silver RT (2016) Management of CML-blast crisis. Best Pract Res Clin Haematol 29:295–307. https://doi.org/10.1016/J.BEHA.2016.10.005

    Article  PubMed  Google Scholar 

  6. Pelloso LAF, Vaz De Campos MG, Nascimento M et al (2005) Chronic myeloid leukemia following kidney transplantation. Leuk Res 29:353–355. https://doi.org/10.1016/J.LEUKRES.2004.07.008

    Article  PubMed  Google Scholar 

  7. Soverini S, Bassan R, Lion T (2019) Treatment and monitoring of Philadelphia chromosome-positive leukemia patients: recent advances and remaining challenges. J Hematol Oncol 12:. https://doi.org/10.1186/S13045-019-0729-2

  8. Stein SJ, Baldwin AS (2011) NF-B suppresses ROS levels in BCR-ABL+ cells to prevent activation of JNK and cell death. Oncogene 30:4557–4566. https://doi.org/10.1038/onc.2011.156

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Sheng Z, Ma L, Sun JE et al (2011) BCR-ABL suppresses autophagy through ATF5-mediated regulation of mTOR transcription. Blood 118:2840–2848. https://doi.org/10.1182/BLOOD-2010-12-322537

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Claudiani S, Apperley JF (2018) The argument for using imatinib in CML. Hematol Am Soc Hematol Educ Progr 2018:161–167. https://doi.org/10.1182/ASHEDUCATION-2018.1.161

    Article  Google Scholar 

  11. Giles FJ, Cortes J, Jones D et al (2007) MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation. Blood 109:500–502. https://doi.org/10.1182/BLOOD-2006-05-025049

    CAS  Article  PubMed  Google Scholar 

  12. Lee BJ (2017) Shah NP (2016) Identification and characterization of activating ABL1 1b kinase mutations: impact on sensitivity to ATP-competitive and allosteric ABL1 inhibitors. Leuk 315(31):1096–1107. https://doi.org/10.1038/leu.2016.353

    CAS  Article  Google Scholar 

  13. Lai WV, Lebas L, Barnes TA et al (2019) Afatinib in patients with metastatic or recurrent HER2-mutant lung cancers: a retrospective international multicentre study. Eur J Cancer 109:28–35. https://doi.org/10.1016/j.ejca.2018.11.030

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Muresan B, Mamolo C, Cappelleri JC, et al (2021) An indirect comparison between bosutinib, nilotinib and dasatinib in first-line chronic phase chronic myeloid leukemia. 37:801–809. https://doi.org/10.1080/03007995.2021.1896489

  15. Reddy MR, Parrill AL (1999) Overview of rational drug design. ACS Symp Ser 719:1–11. https://doi.org/10.1021/bk-1999-0719.ch001

    CAS  Article  Google Scholar 

  16. Lindauer M, Hochhaus A (2018) Dasatinib. In: Recent results in cancer research. Recent Results Cancer Res, pp 29–68

  17. Müller MC, Cortes JE, Kim D-W et al (2009) Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood 114:4944–4953. https://doi.org/10.1182/blood-2009-04-214221

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Soverini S, Martinelli G, Colarossi S et al (2007) Second-line treatment with dasatinib in patients resistant to imatinib can select novel inhibitor-specific BCR-ABL mutants in Ph+ ALL. Lancet Oncol 8:273–274. https://doi.org/10.1016/S1470-2045(07)70078-5

    Article  PubMed  Google Scholar 

  19. Wind S, Schnell D, Ebner T et al (2017) Clinical pharmacokinetics and pharmacodynamics of afatinib. Clin Pharmacokinet 56:235–250. https://doi.org/10.1007/S40262-016-0440-1

    CAS  Article  PubMed  Google Scholar 

  20. Jr RR (2014) The ErbB/HER family of protein-tyrosine kinases and cancer. Pharmacol Res 79:34–74. https://doi.org/10.1016/J.PHRS.2013.11.002

  21. Scheffler M, Kobe C, Zander T et al (2012) Monitoring reversible and irreversible EGFR inhibition with erlotinib and afatinib in a patient with EGFR-mutated non-small cell lung cancer (NSCLC) using sequential [18F]fluorothymidine (FLT-)PET. Lung Cancer 77:617–620. https://doi.org/10.1016/j.lungcan.2012.05.110

    Article  PubMed  Google Scholar 

  22. Dungo RT, Keating GM (2013) Afatinib: first global approval. Drugs 73:1503–1515. https://doi.org/10.1007/s40265-013-0111-6

    CAS  Article  PubMed  Google Scholar 

  23. Hurvitz SA, Shatsky R, Harbeck N (2014) Afatinib in the treatment of breast cancer. Expert Opin Investig Drugs 23:1039–1047. https://doi.org/10.1517/13543784.2014.924505

    CAS  Article  PubMed  Google Scholar 

  24. Keating GM (2014) Afatinib: a review of its use in the treatment of advanced non-small cell lung cancer. Drugs 74:207–221. https://doi.org/10.1007/s40265-013-0170-8

    CAS  Article  PubMed  Google Scholar 

  25. Watanabe K, Kage H, Nagoshi S et al (2020) Dual EGFR and ABL tyrosine kinase inhibitor treatment in a patient with concomitant EGFR-mutated lung adenocarcinoma and BCR-ABL1-positive CML. Case Rep Oncol Med 2020:1–6. https://doi.org/10.1155/2020/4201727

    Article  Google Scholar 

  26. Nagar B, Hantschel O, Young MA et al (2003) Structural basis for the autoinhibition of c-Abl tyrosine kinase. Cell 112:859–871. https://doi.org/10.1016/S0092-8674(03)00194-6

    CAS  Article  PubMed  Google Scholar 

  27. Feige J-J, Chambaz EM (1987) Membrane receptors with protein-tyrosine kinase activity. Biochimie 69:379–385. https://doi.org/10.1016/0300-9084(87)90029-0

    CAS  Article  PubMed  Google Scholar 

  28. Chen VB, Arendall WB, Headd JJ et al (2010) MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr Sect D Biol Crystallogr 66:12–21. https://doi.org/10.1107/S0907444909042073

    CAS  Article  Google Scholar 

  29. Kim K, Jordan KD (2002) Comparison of density functional and MP2 calculations on the water monomer and dimer. J Phys Chem 98:10089–10094. https://doi.org/10.1021/J100091A024

    Article  Google Scholar 

  30. Frisch MJ, Trucksr GW, Schlegel HB, et al (2009) Gaussian 09, Revision D.01. Gaussian

  31. Dennington R, Keith T, Millam J (2007) Gauss view. Version 4(1):2

    Google Scholar 

  32. Zhurko GA (2005) Chemcraft - graphical software for visualization of quantum chemistry

  33. Morris GM, Huey R, Lindstrom W et al (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30:2785–2791. https://doi.org/10.1002/jcc.21256

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph. https://doi.org/10.1016/0263-7855(96)00018-5

    Article  PubMed  Google Scholar 

  35. Wiley EA, MacDonald M, Lambropoulos A et al (2006) LGA-dock/EM-dock exploring Lamarckian genetic algorithms and energy-based local search for ligand receptor docking. Can J Chem 84:384–391. https://doi.org/10.1139/V06-012

    CAS  Article  Google Scholar 

  36. Systèmes D (2015) Discovery studio. BIOVIA

  37. Lu T, Chen F (2012) Multiwfn: a multifunctional wavefunction analyzer. J Comput Chem 33:580–592. https://doi.org/10.1002/jcc.22885

    CAS  Article  PubMed  Google Scholar 

  38. Kiavue N, Cabel L, Melaabi S et al (2019) (2019) ERBB3 mutations in cancer: biological aspects, prevalence and therapeutics. Oncogene 393(39):487–502. https://doi.org/10.1038/s41388-019-1001-5

    CAS  Article  Google Scholar 

  39. Fioressi SE, Bacelo DE (2019) Duchowicz PR (2019) QSAR study of human epidermal growth factor receptor (EGFR) inhibitors: conformation-independent models. Med Chem Res 2811(28):2079–2087. https://doi.org/10.1007/S00044-019-02437-Y

    Article  Google Scholar 

  40. Tokarski JS, Newitt JA, Chang CYJ et al (2006) The structure of dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. Cancer Res 66:5790–5797. https://doi.org/10.1158/0008-5472.CAN-05-4187

    CAS  Article  PubMed  Google Scholar 

  41. Pereira WA, Nascimento ÉCM, Martins JBL (2021) Electronic and structural study of T315I mutated form in DFG-out conformation of BCR-ABL inhibitors. 101080/0739110220211935320. https://doi.org/10.1080/07391102.2021.1935320

  42. Martins P, Jesus J, Santos S, et al (2015) Heterocyclic anticancer compounds: recent advances and the paradigm shift towards the use of nanomedicine’s tool box. Mol 2015, Vol 20, Pages 16852–16891 20:16852–16891. https://doi.org/10.3390/MOLECULES200916852

  43. Park H, Hong S, Kim J, Hong S (2013) Discovery of picomolar ABL kinase inhibitors equipotent for wild type and T315I mutant via structure-based de novo design. J Am Chem Soc 135:8227–8237. https://doi.org/10.1021/JA311756U

    CAS  Article  PubMed  Google Scholar 

  44. Pal D, Chakrabarti P (2001) Non-hydrogen bond interactions involving the methionine sulfur atom. J Biomol Struct Dyn 19:115–128. https://doi.org/10.1080/07391102.2001.10506725

    CAS  Article  PubMed  Google Scholar 

  45. Wishart DS Guo AC, Shrivastava S, Hassanali M, Stothard P, Chang Z, Woolsey J. KC (2006) DrugBank: a comprehensive resource for in silico drug discovery and exploration. In: Nucleic Acids Res.

  46. Scalzulli E, Caocci G, Efficace F et al (2021) Real-life comparison of nilotinib versus dasatinib as second-line therapy in chronic phase chronic myeloid leukemia patients. Ann Hematol 1005(100):1213–1219. https://doi.org/10.1007/S00277-021-04477-0

    Article  Google Scholar 

  47. Ishida Y, Murai K, Yamaguchi K et al (2016) Pharmacokinetics and pharmacodynamics of dasatinib in the chronic phase of newly diagnosed chronic myeloid leukemia. Eur J Clin Pharmacol 72:185–193. https://doi.org/10.1007/s00228-015-1968-y

    CAS  Article  PubMed  Google Scholar 

  48. Akagi T, Murai K, Shimosegawa K et al (2011) Efficacy and safety of dasatinib in chronic myeloid leukemia patients in chronic phase (CML-CP) with imatinib resistance or intolerance. Blood 118:4444. https://doi.org/10.1182/BLOOD.V118.21.4444.4444

    Article  Google Scholar 

  49. Redner RL, Beumer JH, Kropf P et al (2018) A phase-1 study of dasatinib plus all-trans retinoic acid in acute myeloid leukemia. Leuk Lymphoma 59:2595–2601. https://doi.org/10.1080/10428194.2018.1443330

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. Condorelli F, Genazzani AA (2010) Dasatinib BioDrugs 24:157–163. https://doi.org/10.2165/11535870-000000000-00000

    CAS  Article  PubMed  Google Scholar 

  51. Miljus J, Melo JV, Boros L et al (2004) Metabolic profile of imatinib resistance in CML cells. Blood 104:1982. https://doi.org/10.1182/BLOOD.V104.11.1982.1982

    Article  Google Scholar 

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Funding

This work was supported by the Brazilian National Council for Scientific and Technological Development (CNPq 310071/2018–6) and the Foundation for Research of Federal District/Brazil (FAPDF 0193.001642/2017).

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Contributions

Kelvyn M. L. Rocha: Investigation, Calculations, Writing — original draft. Érica C. M. Nascimento: Formal analysis, Methodology. João B. L. Martins: Conceptualization, Formal analysis, Methodology, Resources, Supervision, Writing — review and editing.

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Correspondence to Érica C. M. Nascimento.

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This paper belongs to the Topical Collection VIII Symposium on Electronic Structure and Molecular Dynamics – VIII SeedMol

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Rocha, K.M.L., Nascimento, É.C.M. & Martins, J.B.L. Investigation on the interaction behavior of afatinib, dasatinib, and imatinib docked to the BCR-ABL protein. J Mol Model 27, 309 (2021). https://doi.org/10.1007/s00894-021-04925-8

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  • DOI: https://doi.org/10.1007/s00894-021-04925-8

Keywords

  • CML
  • Afatinib
  • Dasatinib
  • Docking
  • Imatinib
  • NCI