Novel Inhibitors of T315I Mutant BCR-ABL1 Tyrosine Kinase for Chronic Myeloid Leukemia Disease Through Fragment-Based Drug Design

  • Satya Anindita
  • Atika Marnolia
  • Hersal Hermana Putra
  • Muhammad Chandra Haikal
  • Usman Sumo Friend TambunanEmail author
Conference paper
Part of the Lecture Notes in Computer Science book series (LNCS, volume 10847)


The hallmark genetic abnormality of CML is named Philadelphia chromosome. Philadelphia chromosome occurs as a result of recombination of two genes, namely the cellular ABL gene on chromosome 9 and BCR gene located on chromosome 22. The Philadelphia chromosomal translocation is responsible for the ABL and BCR fusion. The ABL and BCR proteins play a central role in the pathogenesis of CML. The malignant transformation by BCR-ABL is critically dependent on its protein tyrosine kinase activity. It makes ABL kinase is an attractive target for therapeutic intervention. In this research, about 653,214 leadlike compounds were obtained from MOE database. The compounds were screened using Data Warrior v.4.6.1 and also docked to predict their binding affinity to BCR-ABL1 tyrosine kinase protein using MOE 2014.09 software. Fragment-based drug design was applied to find a new drug candidate. Finally, five new compounds were generated from this method. The compound LUT-1 has the highest potential due to the low ΔG binding score, acceptable RMSD score, and ADME-Tox result.


CML BCR-ABL1 Docking Fragment-based 



This research is financially supported by the Direktorat of Research and Community Engagement of Universitas Indonesia (DRPM UI) by Hibah Publikasi Internasional Terindeks untuk Tugas Akhir Mahasiswa (PITTA UI) no. 2327/UN2.R3.1/HKP.05.00/2018.


  1. 1.
    Chasseriau, J., Rivet, J., Bilan, F., Chomel, J.C., Guilhot, F., Bourmeyster, N., Kitzis, A.: Characterization of the different BCR-ABL transcripts with a single multiplex RT-PCR. J. Mol. Diagn. 6, 343–347 (2004)CrossRefGoogle Scholar
  2. 2.
    Crisan, D., Carr, E.R.: BCR/abl gene rearrangement in chronic myelogenous leukemia and acute leukemias. Lab. Med. 23, 730–736 (1992)CrossRefGoogle Scholar
  3. 3.
    Medves, S., Demoulin, J.B.: Tyrosine kinase gene fusions in cancer: translating mechanisms into targeted therapies. J. Cell Mol. Med. 16, 237–248 (2012)CrossRefGoogle Scholar
  4. 4.
    Banavath, H.N., Sharma, O.P., Kumar, M.S., Baskaran, R.: Identification of novel tyrosine kinase inhibitors for drug-resistant T315I mutant BCR-ABL: a virtual screening and molecular dynamics simulations study. Sci. Rep. 4, 1–11 (2014)Google Scholar
  5. 5.
    Roche-Lestienne, C., Soenen-Cornu, V., Grardel-Duflos, N., Laï, J.L., Philippe, N., Facon, T., Fenaux, P., Preudhomme, C.: Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment. Blood 100, 1014–1018 (2002)CrossRefGoogle Scholar
  6. 6.
    Soverini, S., Hochhaus, A., Nicolini, F.E., Gruber, F., Lange, T., Saglio, G., Pane, F., Mu, M.C., Ernst, T., Rosti, G., Porkka, K., Baccarani, M., Cross, N.C.P., Martinelli, G.: BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood 118, 1208–1215 (2011)CrossRefGoogle Scholar
  7. 7.
    Pemovska, T., Johnson, E., Kontro, M., Repasky, G.A., Chen, J., Wells, P., Cronin, C.N., Mctigue, M., Kallioniemi, O., Porkka, K., Murray, B.W., Wennerberg, K.: Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation. Nature 519, 102–105 (2015)CrossRefGoogle Scholar
  8. 8.
    Erlanson, D.A.: Introduction to fragment-based drug discovery. Top. Curr. Chem. 317, 1–32 (2012)Google Scholar
  9. 9.
    Chan, W.W., Wise, S.C., Kaufman, M.D., Ahn, Y.M., Ensinger, C.L., Haack, T., Hood, M.M., Jones, J., Lord, J.W., Lu, W.P., Miller, D., Patt, W.C., Smith, B.D., Petillo, P.A., Rutkoski, T.J., Telikepalli, H., Vogeti, L., Yao, T., Chun, L., Clark, R., Evangelista, P., Gavrilescu, L.C., Lazarides, K., Zaleskas, V.M., Stewart, L.J., Van Etten, R.A., Flynn, D.L.: Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036. Cancer Cell 19, 556–568 (2011)CrossRefGoogle Scholar
  10. 10.
    Tambunan, U.S.F., Toepak, E.: In silico design of fragment-based drug targeting host processing α-glucosidase I for dengue fever, vol. 172, pp. 1–10. IOP Publishing Ltd (2017)Google Scholar
  11. 11.
    Congreve, M., Carr, R., Murray, C., Jhoti, H.: A “rule of three” for fragment-based lead discovery? Drug Discov. Ther. 8, 876–877 (2003)CrossRefGoogle Scholar
  12. 12.
    Lipinski, C.A., Lombardo, F., Dominy, B.W., Feeney, P.J.: Experimental and computational approaches to estimate solubility and permeability in drug discovery and development setting. Adv. Drug Deliv. Rev. 46, 3–26 (2001)CrossRefGoogle Scholar
  13. 13.
    Veber, D.F., Johnson, S.R., Cheng, H., Smith, B.R., Ward, K.W., Kopple, K.D.: Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem. 45, 2615–2623 (2002)CrossRefGoogle Scholar
  14. 14.
    Daina, A., Michielin, O., Zoete, V.: SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 7, 1–13 (2017)CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Satya Anindita
    • 1
  • Atika Marnolia
    • 1
  • Hersal Hermana Putra
    • 1
  • Muhammad Chandra Haikal
    • 1
  • Usman Sumo Friend Tambunan
    • 1
    Email author
  1. 1.Faculty of Mathematics and Natural SciencesUniversitas IndonesiaDepokIndonesia

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