Skip to main content
SpringerLink
Log in

Identification of common inhibitors of wild-type and T315I mutant of BCR-ABL through the parallel structure-based virtual screening

  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Abstract

Although the constitutively activated break-point cluster region-Abelson (BCR-ABL) tyrosine kinase was well known to be responsible for chronic myelogenous leukemia (CML), the existence of drug-resistant mutants of BCR-ABL has made it difficult to develop effective anti-CML drugs. Here, we report the first example for a successful application of the structure-based virtual screening to identify two common inhibitors equipotent for the wild type and the most drug-resistant T315I mutant of BCR-ABL. Because both inhibitors were screened for having desirable physicochemical properties as a drug candidate and revealed micromolar inhibitory activities, they deserve consideration for further development by structure–activity relationship (SAR) studies to optimize the anti-CML activity. We also address the structural features relevant to the stabilizations of the identified inhibitors in the ATP-binding sites. The results indicate that the inhibitors should be less stabilized by the hydrogen-bond interactions with the change of the receptor from the wild type to T315I mutant due to the replacement of the hydroxy group with the ethyl moiety in the ATP-binding site. Nonetheless, the inhibitors are found to be capable of maintaining the potency for the mutant through the strengthening of hydrophobic interactions to the extent sufficient to compensate for the loss of some hydrogen bonds. This differential binding mode may serve as key information for designing new common inhibitors of the wild type and T315I mutant of BCR-ABL.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Quintas-Cardama A, Cortes J (2009) Molecular biology of bcr-abl1-positive chronic myeloid leukemia. Blood 113:1619–1630

    Article  CAS  Google Scholar 

  2. Eck MJ, Manley PW (2009) The interplay of structural information and functional studies in kinase drug design: insights from BCR-Abl. Curr Opin Cell Biol 21:288–295

    Article  CAS  Google Scholar 

  3. Schenone S, Bruno O, Radi M, Botta M (2010) New insights into small-molecule inhibitors of Bcr-Abl. Med Res Rev 31:1–41

    Article  Google Scholar 

  4. Capdeville R, Buchdunger E, Zimmermann J, Matter A (2002) Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat Rev Drug Discov 1:493–503

    Article  CAS  Google Scholar 

  5. O’Hare T, Eide CA, Deininger MW (2007) Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood 110:2242–2249

    Article  Google Scholar 

  6. Quintas-Cardama A, Kantarjian H, Cortes J (2007) Flying under the radar: the new wave of BCR-ABL inhibitors. Nat Rev Drug Discov 6:834–848

    Article  CAS  Google Scholar 

  7. Lombardo LJ, Lee FY, Chen P, Norris D, Barrish JC, Behnia K, Castaneda S, Cornelius LAM, Das J, Doweyko AM, Fairchild C, Hunt JT, Inigo I, Johnston K, Kamath A, Kan D, Klei H, Marathe P, Pang S, Peterson R, Pitt S, Schieven GL, Schmidt RJ, Tokarski J, Wen ML, Wityak J, Borzilleri RM (2004) Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 47:6658–6661

    Article  CAS  Google Scholar 

  8. Weisberg E, Manley PW, Breitenstein W, Brüggen J, Cowan-Jacob SW, Ray A, Huntly B, Fabbro D, Fendrich G, Hall-Meyers E, Kung AL, Mestan J, Daley GQ, Callahan L, Catley L, Cavazza C, Azam M, Neuberg D, Wright RD, Gilliland DG, Griffin JD (2005) Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 7:129–141

    Article  CAS  Google Scholar 

  9. Kimura S, Naito H, Segawa H, Kuroda J, Yuasa T, Sato K, Yokota A, Kamitsuji Y, Kawata E, Ashihara E, Nakaya Y, Naruoka H, Wakayama T, Nasu K, Asaki T, Niwa T, Hirabayashi K, Maekawa T (2005) NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia. Blood 106:3948–3954

    Article  CAS  Google Scholar 

  10. Boschelli DH, Ye F, Wang YD, Dutia M, Johnson SL, Wu B, Miller K, Powell DW, Yaczko D, Young M, Tischler M, Arndt K, Discafani C, Etienne C, Gibbons J, Grod J, Lucas J, Weber JM, Boschelli F (2001) Optimization of 4-phenylamino-3-quinolinecarbonitriles as potent inhibitors of Src kinase activity. J Med Chem 44:3965–3977

    Article  CAS  Google Scholar 

  11. Zhou T, Parillon L, Li F, Wang Y, Keats J, Lamore S, Xu Q, Shakespeare W, Dalgarno D, Zhu X (2007) Crystal structure of the T315I mutant of Abl kinase. Chem Biol Drug Des 70:171–181

    Article  CAS  Google Scholar 

  12. Giles FJ, Cortes J, Jones D, Bergstrom D, Kantarjian H, Freedman SJ (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

    Article  CAS  Google Scholar 

  13. Gontarewicz A, Balabanov S, Keller G, Colombo R, Graziano A, Pesenti E, Benten D, Bokemeyer C, Fiedler W, Moll J, Brümmendorf TH (2008) Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I. Blood 111:4355–4364

    Article  CAS  Google Scholar 

  14. Howard S, Berdini V, Boulstridge JA, Carr MG, Cross DM, Curry J, Devine LA, Early TR, Fazal L, Gill AL, Heathcote M, Maman S, Matthews JE, McMenamin RL, Navarro EF, O’Brien MA, O’Reilly M, Rees DC, Reule M, Tisi D, Williams G, Vinković M, Wyatt PG (2009) Fragment-based discovery of the pyrazol-4-yl urea (AT9283), a multitargeted kinase inhibitor with potent aurora kinase activity. J Med Chem 52:379–388

    Article  CAS  Google Scholar 

  15. Shiotsu Y, Kiyoi H, Ishikawa Y, Tanizaki R, Shimizu M, Umehara H, Ishii K, Mori Y, Ozeki K, Minami Y, Abe A, Maeda H, Akiyama T, Kanda Y, Sato Y, Akinaga S, Naoe T (2009) KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation. Blood 114:1607–1617

    Article  CAS  Google Scholar 

  16. Quintas-Cardama A, Cortes J (2008) Therapeutic options against BCR-ABL1 T315I positive chronic myelogenous leukemia. Clin Cancer Res 14:4392–4399

    Article  CAS  Google Scholar 

  17. Choi HG, Ren P, Adrian F, Sun F, Lee HS, Wang X, Ding Q, Zhang G, Xie Y, Zhang J, Liu Y, Tuntland T, Warmuth M, Manley PW, Mestan J, Gray NS, Sim T (2010) A type-II kinase inhibitor capable of inhibiting the T315I “gatekeeper” mutant of Bcr-Abl. J Med Chem 53:5439–5448

    Article  CAS  Google Scholar 

  18. Huang WS, Metcalf CA, Sundaramoorthi R, Wang Y, Zou D, Thomas RM, Zhu X, Cai L, Wen D, Liu S, Romero J, Qi J, Chen I, Banda G, Lentini SP, Das S, Xu Q, Keats J, Wang F, Wardwell S, Ning Y, Snodgrass JT, Broudy MI, Russian K, Zhou T, Commodore L, Narasimhan NI, Mohemmad QK, Iuliucci J, Rivera VM, Dalgarno DC, Sawyer TK, Clackson T, Shakespeare WC (2010) Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant. J Med Chem 53:4701–4719

    Article  CAS  Google Scholar 

  19. Thomas M, Huang WS, Wen D, Zhu X, Wang Y, Metcalf CA, Liu S, Chen I, Romero J, Zou D, Sundaramoorthi R, Li F, Qi J, Cai L, Zhou T, Commodore L, Xu Q, Keats J, Wang F, Wardwell S, Ning Y, Snodgrass JT, Broudy MI, Russian K, Iuliucci J, Rivera VM, Sawyer TK, Dalgarno DC, Clackson T, Shakespeare WC (2011) Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR–ABL including the T315I gatekeeper mutant. Bioorg Med Chem Lett 21:3743–3748

    Article  CAS  Google Scholar 

  20. Deng X, Lim SM, Zhang J, Gray NS (2010) Broad spectrum alkynyl inhibitors of T315I Bcr-Abl. Bioorg Med Chem Lett 20:4196–4200

    Article  CAS  Google Scholar 

  21. Cao J, Fine R, Gritzen C, Hood J, Kang X, Klebansky B, Lohse D, Mak CC, McPherson A, Noronha G, Palanki MSS, Pathak VP, Renick J, Soll R, Zeng B, Zhu H (2007) The design and preliminary structure–activity relationship studies of benzotriazines as potent inhibitors of Abl and Abl-T315I enzymes. Bioorg Med Chem Lett 17:5812–5818

    Article  CAS  Google Scholar 

  22. Gambacorti-Passerini C, Gasser M, Ahmed S, Assouline S, Scapozza L (2005) Abl inhibitor BMS354825 binding mode in Abelson kinase revealed by molecular docking studies. Leukemia 19:1267–1269

    Article  CAS  Google Scholar 

  23. Lü S, Luo Q, Hao X, Li X, Ji L, Zheng W, Wang F (2011) Synthesis and docking study of 2-phenylaminopyrimidine Abl tyrosine kinase inhibitors. Bioorg Med Chem Lett 21:6964–6968

    Article  Google Scholar 

  24. Wang D, Zhang Z, Lu X, Feng Y, Luo K, Gan J, Yingxue L, Wan J, Li X, Zhang F, Tu Z, Cai Q, Ren X, Ding K (2011) Hybrid compounds as new Bcr/Abl inhibitors. Bioorg Med Chem Lett 21:1965–1968

    Article  CAS  Google Scholar 

  25. Warren GL, Andrews CW, Capelli AM, Clarke B, LaLonde J, Lambert MH, Lindvall M, Nevins N, Semus SF, Senger S, Tedesco G, Wall ID, Woolven JM, Peishoff CE, Head MS (2006) A critical assessment of docking programs and scoring functions. J Med Chem 49:5912–5931

    Article  CAS  Google Scholar 

  26. Shoichet BK, Leach AR, Kuntz ID (1999) Ligand solvation in molecular docking. Proteins 34:4–16

    Article  CAS  Google Scholar 

  27. Nagar B, Bornmann W, Pellicena P, Schindler T, Veach DR, Miller WT, Clarkson B, Kuriyan J (2002) Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). Cancer Res 62:4236–4243

    CAS  Google Scholar 

  28. O’Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, Adrian LT, Zhou T, Huang WS, Xu Q, Metcalf CA, Tyner JW, Loriaux MM, Corbin AS, Wardwell S, Ning Y, Keats JA, Wang Y, Sundaramoorthi R, Thomas M, Zhou D, Snodgrass J, Commodore L, Sawyer TK, Dalgarno DC, Deininger MW, Druker BJ, Clackson T (2009) AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 16:401–412

    Article  Google Scholar 

  29. Jeffrey GA (1997) An introduction to hydrogen bonding. Oxford University Press, Oxford

    Google Scholar 

  30. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliver Rev 23:3–25

    Article  CAS  Google Scholar 

  31. Gasteiger J, Marsili M (1980) Iterative partial equalization of orbital electronegativity—a rapid access to atomic charges. Tetrahedron 36:3219–3228

    Article  CAS  Google Scholar 

  32. Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 19:1639–1662

    Article  CAS  Google Scholar 

  33. Park H, Lee J, Lee S (2006) Critical assessment of the automated AutoDock as a new docking tool for virtual screening. Proteins 65:549–554

    Article  CAS  Google Scholar 

  34. Park H, Jeon YH (2007) Cubic equation governing the outer-region dielectric constant of globular proteins. Phys Rev E 75:021916

    Article  Google Scholar 

  35. Stouten PFW, Frömmel C, Nakamura H, Sander C (1993) An effective solvation term based on atomic occupancies for use in protein simulations. Mol Simul 10:97–120

    Article  CAS  Google Scholar 

  36. Kang H, Choi H, Park H (2007) Prediction of molecular solvation free energy based on the optimization of atomic solvation parameters with genetic algorithm. J Chem Inf Model 47:509–514

    Article  CAS  Google Scholar 

  37. Park H, Jeon JY, Kim SY, Jeong DG, Ryu SE (2011) Identification of novel inhibitors of mitogen-activated protein kinase phosphatase-1 with structure-based virtual screening. J Comput Aided Mol Des 25:469–475

    Article  CAS  Google Scholar 

  38. Park H, Chi O, Kim J, Hong S (2011) Identification of novel inhibitors of tropomyosin-related kinase A through the structure-based virtual screening with homology-modeled protein structure. J Chem Inf Model 51:2986–2993

    Article  CAS  Google Scholar 

  39. Fabian MA, Biggs WH III, Treiber DK, Atteridge CE, Azimioara MD, Bendetti MG, Carter TA, Ciceri P, Edeen PT, Floyd M, Ford JM, Galvin M, Gerlach JL, Grotzfeld RM, Herrgard S, Insko DE, Insko MA, Lai AG, Lelias JM, Mehta SA, Milanov ZV, Velasco AM, Wodicka LM, Patel HK, Zarrinkar PP, Lockhart DJ (2005) A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 23:329–336

    Article  CAS  Google Scholar 

  40. Hassan AQ, Sharma SV, Warmuth M (2010) Allosteric inhibition of BCR-ABL. Cell Cycle 9:3710–3714

    Google Scholar 

Download references

Acknowledgments

We could perform this study with the financial support by Basic Science Research Program through National Research Foundation of Korea (NRF) funded by Ministry of Education, Science and Technology (2011-0022858). This research was also supported by NRF funded by Ministry of Education, Science and Technology (NRF-2011-2011-0026680, 2011-0016436 and 2011-0020322).

Author information

Authors and Affiliations

  1. Department of Bioscience and Biotechnology, Sejong University, 98 Kunja-Dong, Kwangjin-Ku, Seoul, 143-747, Korea

    Hwangseo Park

  2. Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Taejon, 305-701, Korea

    Seunghee Hong & Sungwoo Hong

Authors
  1. Hwangseo Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Seunghee Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sungwoo Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Hwangseo Park or Sungwoo Hong.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 69 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Park, H., Hong, S. & Hong, S. Identification of common inhibitors of wild-type and T315I mutant of BCR-ABL through the parallel structure-based virtual screening. J Comput Aided Mol Des 26, 983–992 (2012). https://doi.org/10.1007/s10822-012-9593-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-012-9593-7

Keywords

Search

Navigation