Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized at the molecular level by the expression of Bcr-abl, a 210-kDa fusion protein with deregulated tyrosine kinase activity. Encouraged by the clinical validation of Bcr-abl as the target for the treatment of CML by imatinib, we sought to identify pharmacological agents that could target this kinase by a distinct mechanism. We report the discovery of a new class of Bcr-abl inhibitors using an unbiased differential cytotoxicity screen of a combinatorial kinase-directed heterocycle library. Compounds in this class (exemplified by GNF-2) show exclusive antiproliferative activity toward Bcr-abl–transformed cells, with potencies similar to imatinib, while showing no inhibition of the kinase activity of full-length or catalytic domain of c-abl. We propose that this new class of compounds inhibits Bcr-abl kinase activity through an allosteric non-ATP competitive mechanism.
Subscribe to Journal
Get full journal access for 1 year
only $14.08 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Protein Data Bank
Schindler, T. et al. Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science 289, 1938–1942 (2000).
Gorre, M.E. et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293, 876–880 (2001).
von Bubnoff, N., Schneller, F., Peschel, C. & Duyster, J. BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: a prospective study. Lancet 359, 487–491 (2002).
Cowan-Jacob, S.W. et al. Imatinib (STI571) resistance in chronic myelogenous leukemia: molecular basis of the underlying mechanisms and potential strategies for treatment. Mini Rev. Med. Chem. 4, 285–299 (2004).
Weisberg, E. et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 7, 129–141 (2005).
Shah, N.P. et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305, 399–401 (2004).
Superti-Furga, G. & Courtneidge, S.A. Structure-function relationships in Src family and related protein tyrosine kinases. Bioessays 17, 321–330 (1995).
Nagar, B. et al. Structural basis for the autoinhibition of c-Abl tyrosine kinase. Cell 112, 859–871 (2003).
Barker, A.J. et al. Studies leading to the identification of ZD1839 (IRESSA): an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor targeted to the treatment of cancer. Bioorg. Med. Chem. Lett. 11, 1911–1914 (2001).
Meijer, L. et al. Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur. J. Biochem. 243, 527–536 (1997).
Buchdunger, E. et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res. 56, 100–104 (1996).
Regan, J. et al. Pyrazole urea-based inhibitors of p38 MAP kinase: from lead compound to clinical candidate. J. Med. Chem. 45, 2994–3008 (2002).
Lyons, J.F., Wilhelm, S., Hibner, B. & Bollag, G. Discovery of a novel Raf kinase inhibitor. Endocr. Relat. Cancer 8, 219–225 (2001).
Lowinger, T.B., Riedl, B., Dumas, J. & Smith, R.A. Design and discovery of small molecules targeting raf-1 kinase. Curr. Pharm. Des. 8, 2269–2278 (2002).
Ohren, J.F. et al. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat. Struct. Mol. Biol. 11, 1192–1197 (2004).
Barnett, S.F. et al. Identification and characterization of pleckstrin-homology-domain-dependent and isoenzyme-specific Akt inhibitors. Biochem. J. 385, 399–408 (2005).
Grimsby, J. et al. Allosteric activators of glucokinase: potential role in diabetes therapy. Science 301, 370–373 (2003).
Ding, S., Gray, N.S., Wu, X., Ding, Q. & Schultz, P.G. A combinatorial scaffold approach toward kinase-directed heterocycle libraries. J. Am. Chem. Soc. 124, 1594–1596 (2002).
Goldman, J.M. & Melo, J.V. Chronic myeloid leukemia–advances in biology and new approaches to treatment. N. Engl. J. Med. 349, 1451–1464 (2003).
Druker, B.J. et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat. Med. 2, 561–566 (1996).
Carroll, M. et al. CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins. Blood 90, 4947–4952 (1997).
Dorsey, J.F. et al. Interleukin-3 protects Bcr-Abl-transformed hematopoietic progenitor cells from apoptosis induced by Bcr-Abl tyrosine kinase inhibitors. Leukemia 16, 1589–1595 (2002).
Hantschel, O. et al. A myristoyl/phosphotyrosine switch regulates c-Abl. Cell 112, 845–857 (2003).
Chou, T.C. & Talalay, P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Regul. 22, 27–55 (1984).
von Bubnoff, N. et al. Inhibition of wild-type and mutant Bcr-Abl by pyrido-pyrimidine-type small molecule kinase inhibitors. Cancer Res. 63, 6395–6404 (2003).
Burke, J.R. et al. BMS-345541 is a highly selective inhibitor of IκB kinase that binds at an allosteric site of the enzyme and blocks NF-κB-dependent transcription in mice. J. Biol. Chem. 278, 1450–1456 (2003).
Nardi, V., Azam, M. & Daley, G.Q. Mechanisms and implications of imatinib resistance mutations in BCR-ABL. Curr. Opin. Hematol. 11, 35–43 (2004).
Huse, M. & Kuriyan, J. The conformational plasticity of protein kinases. Cell 109, 275–282 (2002).
Capdeville, R., Buchdunger, E., Zimmermann, J. & Matter, A. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat. Rev. Drug Discov. 1, 493–502 (2002).
Klejman, A., Rushen, L., Morrione, A., Slupianek, A. & Skorski, T. Phosphatidylinositol-3 kinase inhibitors enhance the anti-leukemia effect of STI571. Oncogene 21, 5868–5876 (2002).
Sun, X., Layton, J.E., Elefanty, A. & Lieschke, G.J. Comparison of effects of the tyrosine kinase inhibitors AG957, AG490, and STI571 on BCR-ABL–expressing cells, demonstrating synergy between AG490 and STI571. Blood 97, 2008–2015 (2001).
Topaly, J., Zeller, W.J. & Fruehauf, S. Synergistic activity of the new ABL-specific tyrosine kinase inhibitor STI571 and chemotherapeutic drugs on BCR-ABL-positive chronic myelogenous leukemia cells. Leukemia 15, 342–347 (2001).
Gumireddy, K. et al. A non-ATP-competitive inhibitor of BCR-ABL overrides imatinib resistance. Proc. Natl. Acad. Sci. USA 102, 1992–1997 (2005).
Branford, S. et al. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood 102, 276–283 (2003).
Danhauser-Riedl, S., Warmuth, M., Druker, B.J., Emmerich, B. & Hallek, M. Activation of Src kinases p53/56lyn and p59hck by p210bcr/abl in myeloid cells. Cancer Res. 56, 3589–3596 (1996).
We thank J.D. Griffin, G. Gilliland, R. Salgia and J. Duyster for kindly providing us with cell lines, and C. Trussell, D. Kemp, M. Warmuth and S. Kim for their help and valuable discussions.
The authors declare no competing financial interests.
About this article
Cite this article
Adrián, F., Ding, Q., Sim, T. et al. Allosteric inhibitors of Bcr-abl–dependent cell proliferation. Nat Chem Biol 2, 95–102 (2006). https://doi.org/10.1038/nchembio760
Cell Chemical Biology (2020)
The specificity of asciminib, a potential treatment for chronic myeloid leukemia, as a myristate-pocket binding ABL inhibitor and analysis of its interactions with mutant forms of BCR-ABL1 kinase
Leukemia Research (2020)
Trends in Pharmacological Sciences (2020)
Angewandte Chemie (2020)
Mini-Reviews in Medicinal Chemistry (2020)