Novel Inhibitors of T315I Mutant BCR-ABL1 Tyrosine Kinase for Chronic Myeloid Leukemia Disease Through Fragment-Based Drug Design
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.
KeywordCML 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.
- 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.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.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
- 8.Erlanson, D.A.: Introduction to fragment-based drug discovery. Top. Curr. Chem. 317, 1–32 (2012)Google Scholar
- 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.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