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Paul Ehrlich's magic bullet concept: 100 years of progress
Nature Reviews Cancervolume 8, pages473–480 (2008)Cite this article
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Abstract
Exceptional advances in molecular biology and genetic research have expedited cancer drug development tremendously. The declared paradigm is the development of 'personalized and tailored drugs' that precisely target the specific molecular defects of a cancer patient. It is therefore appropriate to revisit the intellectual foundations of the development of such agents, as many have shown great clinical success. One hundred years ago, Paul Ehrlich, the founder of chemotherapy, received the Nobel Prize for Physiology or Medicine. His postulate of creating 'magic bullets' for use in the fight against human diseases inspired generations of scientists to devise powerful molecular cancer therapeutics.
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References
Ehrlich, P.Beiträge zur Theorie und Praxis der histologischen Färbung. Thesis, Univ. Leipzig (1878) (in German).
Ehrlich, P. Aus Theorie und Praxis der Chemotherapie.Folia Serologica7, 697–714 (1911) (in German).
Bäumler, E. Paul Ehrlich. Forscher für das Leben. 3rd edn (Minerva, Frankfurt am Main, 1997) (in German).
Ehrlich, P. Die Wertbemessung des Diphterie-heilserums und deren theoretische Grundlagen.Klinisches Jahrbuch6, 299–326 (1897) (in German).
Ehrlich, P. Croonian lecture: on immunity with special reference to cell life.Proc. Roy. Soc. London66, 424–448 (1900).
Ehrlich, P. & Morgenroth, J. Die Seitenkettentheorie der Immunität. Anleitung zu hygienischen Untersuchungen: nach den im Hygienischen Institut der königl. Ludwig-Maximilians-Universität zu München üblichen Methoden zusammengestellt, 3 Aufl.3, 381–394 (1902) (in German).
Ehrlich, P. & Morgenroth, J. Wirkung und Entstehung der aktiven Stoffe im Serum nach der Seiten-kettentheorie.Handbuch der pathogenen Mikroorganismen1, 430–451 (1904) (in German).
Ehrlich, P. Partial cell functions: Nobel lecture, December 11, 1908 inPhysiology or Medicine: including presentation speeches and laureates' biographies 1901–1921 (Elsevier Publishing, Amsterdam, 1967).
Ehrlich, P. & Morgenroth, J. Ueber Haemolysine: dritte Mittheilung.Berliner klinische Wochenschrift37, 453–458 (1900) (in German).
Ehrlich, P. & Sachs, H. Ueber den Mechanismus der Antiamboceptorwirkung.Berliner klinische Wochenschrift 557–558 (1905) (in German).
Ehrlich, P. Chemotherapeutische Trypanosomen-Studien.Berliner klinische Wochenschrift44, 233–236 (1907) (in German).
Ehrlich, P. Die Behandlung der Syphilis mit dem Ehrlichschen Präparat 606.Deutsche medizinische Wochenschrift 1893–1896 (1910) (in German).
Fleming, A., Voureka, A., Kramer, I. R. & Hughes, W. H. The morphology and motility ofProteus vulgaris and other organisms cultured in the presence of penicillin.J. Gen. Microbiol.4, 257–269 (1950).
Goodman, L. S. et al. Landmark article Sept. 21, 1946: Nitrogen mustard therapy. Use of methyl-bis(beta-chloroethyl)amine hydrochloride and tris(beta-chloroethyl)amine hydrochloride for Hodgkin's disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders.JAMA251, 2255–2261 (1984).
Gilman, A. & Philips, F. S. The biological actions and therapeutic applications of the B-chloroethyl amines and sulfides.Science103, 409–436 (1946).
Karnofsky, D. A. Nitrogen mustards in the treatment of neoplastic disease.Adv. Intern. Med.4, 1–75 (1950).
Gilman, A. The initial clinical trial of nitrogen mustard.Am. J. Surg.105, 574–578 (1963).
Watson, J. D. & Crick, F. H. Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid.Nature171, 737–738 (1953).
Heidelberger, C. et al. Fluorinated pyrimidines, a new class of tumour-inhibitory compounds.Nature179, 663–666 (1957).
Kohn, K. W., Spears, C. L. & Doty, P. Inter-strand crosslinking of DNA by nitrogen mustard.J. Mol. Biol.19, 266–288 (1966).
Whittington, R. M. & Close, H. P. Clinical experience with mitomycin C (NSC-26980).Cancer Chemother. Rep.54, 195–198 (1970).
Crooke, S. T. & Bradner, W. T. Bleomycin, a review.J. Med.7, 333–428 (1976).
Rosenberg, B., Vancamp, L. & Krigas, T. Inhibition of cell division inEscherichia coli by electrolysis products from a platinum electrode.Nature205, 698–699 (1965).
Farber, S., Diamond, L. K., Mercer, R. D., Sylvester, R. F. & Wolff, J. R. Temporary remissions in acute leukemia in children produced by folic antagonist, 4-aminopteroylglutamic acid (aminopterin).N. Engl. J. Med.238, 787–793 (1948).
Hitchings, G. H. & Elion, G. B. The chemistry and biochemistry of purine analogs.Ann. NY Acad. Sci.60, 195–199 (1954).
Ehrlich, P. Chemotherapeutic studies on trypanosomes.J. Roy. Inst. Pub. Health15, 449–456 (1907).
Frei, E. III et al. A comparative study of two regimens of combination chemotherapy in acute leukemia.Blood13, 1126–1148 (1958).
Frei, E. III. A commentary. Selected considerations regarding chemotherapy as adjuvant in cancer treatment.Cancer Chemother. Rep.50, 1–8 (1966).
Frei, E. III, DeVita, V. T., Moxley, J. H. III & Carbone, P. P. Approaches to improving the chemotherapy of Hodgkin's disease.Cancer Res.26, 1284–1289 (1966).
Vogelstein, B. & Kinzler, K. W. Cancer genes and the pathways they control.Nature Med.10, 789–799 (2004).
Hanahan, D. & Weinberg, R. A. The hallmarks of cancer.Cell100, 57–70 (2000).
Druker, B. J. et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells.Nature Med.2, 561–566 (1996).
Bartram, C. R. et al. Translocation of c-ab1 oncogene correlates with the presence of a Philadelphia chromosome in chronic myelocytic leukaemia.Nature306, 277–280 (1983).
Felsher, D. W. Cancer revoked: oncogenes as therapeutic targets.Nature Rev. Cancer3, 375–380 (2003).
de Carcer, G., de Castro, I. P. & Malumbres, M. Targeting cell cycle kinases for cancer therapy.Curr. Med. Chem.14, 969–985 (2007).
Santamaria, D. et al. Cdk1 is sufficient to drive the mammalian cell cycle.Nature448, 811–815 (2007).
Holtrich, U. et al. Induction and down-regulation of PLK, a human serine/threonine kinase expressed in proliferating cells and tumors.Proc. Natl Acad. Sci. USA91, 1736–1740 (1994).
Strebhardt, K. & Ullrich, A. Targeting polo-like kinase 1 for cancer therapy.Nature Rev. Cancer6, 321–330 (2006).
Spankuch-Schmitt, B., Bereiter-Hahn, J., Kaufmann, M. & Strebhardt, K. Effect of RNA silencing of polo-like kinase 1 (PLK1) on apoptosis and spindle formation in human cancer cells.J. Natl Cancer Inst.94, 1863–1877 (2002).
Kappel, S., Matthess, Y., Zimmer, B., Kaufmann, M. & Strebhardt, K. Tumor inhibition by genomically integrated inducible RNAi-cassettes.Nucleic Acids Res.34, 4527–4536 (2006).
Blum, G., Gazit, A. & Levitzki, A. Substrate competitive inhibitors of IGF-1 receptor kinase.Biochemistry39, 15705–15712 (2000).
Vassilev, L. T. et al.In vivo activation of the p53 pathway by small-molecule antagonists of MDM2.Science303, 844–848 (2004).
Reindl, W., Yuan, J., Kramer, A., Strebhardt, K. & Berg, T. Inhibition of Polo-like kinase 1 by blocking polo-box domain-dependent protein-protein interactions.Chem. Biol. (in the press).
Fong, T. A. et al. SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types.Cancer Res.59, 99–106 (1999).
Jubb, A. M., Oates, A. J., Holden, S. & Koeppen, H. Predicting benefit from anti-angiogenic agents in malignancy.Nature Rev. Cancer6, 626–635 (2006).
Millauer, B. et al. High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis.Cell72, 835–846 (1993).
Millauer, B., Shawver, L. K., Plate, K. H., Risau, W. & Ullrich, A. Glioblastoma growth inhibitedin vivo by a dominant-negative Flk-1 mutant.Nature367, 576–579 (1994).
Faivre, S., Demetri, G., Sargent, W. & Raymond, E. Molecular basis for sunitinib efficacy and future clinical development.Nature Rev. Drug Discov.6, 734–745 (2007).
Bolden, J. E., Peart, M. J. & Johnstone, R. W. Anticancer activities of histone deacetylase inhibitors.Nature Rev. Drug Discov.5, 769–784 (2006).
Atmaca, A. et al. Valproic acid (VPA) in patients with refractory advanced cancer: a dose escalating phase I clinical trial.Br. J. Cancer97, 177–182 (2007).
Gojo, I. et al. Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias.Blood109, 2781–2790 (2007).
Karagiannis, T. C. & El Osta, A. Will broad-spectrum histone deacetylase inhibitors be superseded by more specific compounds?Leukemia21, 61–65 (2007).
Jameel, A. et al. Clinical and biological significance of HSP89 α in human breast cancer.Int. J. Cancer50, 409–415 (1992).
Yano, M., Naito, Z., Tanaka, S. & Asano, G. Expression and roles of heat shock proteins in human breast cancer.Jpn. J. Cancer Res.87, 908–915 (1996).
Whitesell, L. & Lindquist, S. L. HSP90 and the chaperoning of cancer.Nature Rev. Cancer5, 761–772 (2005).
Ramanathan, R. K. et al. Phase I and pharmacodynamic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with refractory advanced cancers.Clin. Cancer Res.13, 1769–1774 (2007).
Solit, D. B. et al. Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer.Clin. Cancer Res.13, 1775–1782 (2007).
Bagatell, R. et al. Phase I pharmacokinetic and pharmacodynamic study of 17-N-allylamino-17-demethoxygeldanamycin in pediatric patients with recurrent or refractory solid tumors: a pediatric oncology experimental therapeutics investigators consortium study.Clin. Cancer Res.13, 1783–1788 (2007).
Ehrlich, P. Über den jetzigen Stand der Karzinomforschung.Beiträge zur experimentellen Pathologie und Chemotherapie 117–164 (1909) (in German).
Kohler, G. & Milstein, C. Continuous cultures of fused cells secreting antibody of predefined specificity.Nature256, 495–497 (1975).
Carter, P. Improving the efficacy of antibody-based cancer therapies.Nature Rev. Cancer1, 118–129 (2001).
Schrama, D., Reisfeld, R. A. & Becker, J. C. Antibody targeted drugs as cancer therapeutics.Nature Rev. Drug Discov.5, 147–159 (2006).
Slamon, D. J. et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene.Science235, 177–182 (1987).
Slamon, D. J. et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer.Science244, 707–712 (1989).
Maloney, D. G. et al. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma.Blood90, 2188–2195 (1997).
McLaughlin, P. et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program.J. Clin. Oncol.16, 2825–2833 (1998).
Cartron, G. et al. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcγRIIIa gene.Blood99, 754–758 (2002).
Di Gaetano, N. et al. Complement activation determines the therapeutic activity of rituximabin vivo.J. Immunol.171, 1581–1587 (2003).
van Mierlo, G. J. et al. CD40 stimulation leads to effective therapy of CD40− tumors through induction of strong systemic cytotoxic T lymphocyte immunity.Proc. Natl Acad. Sci. USA99, 5561–5566 (2002).
Czuczman, M. S. et al. Phase I/II study of galiximab, an anti-CD80 antibody, for relapsed or refractory follicular lymphoma.J. Clin. Oncol.23, 4390–4398 (2005).
Galizia, G. et al. Cetuximab, a chimeric human mouse anti-epidermal growth factor receptor monoclonal antibody, in the treatment of human colorectal cancer.Oncogene26, 3654–3660 (2007).
Jonker, D. J. et al. Cetuximab for the treatment of colorectal cancer.N. Engl. J. Med.357, 2040–2048 (2007).
Herbst, R. S., Fukuoka, M. & Baselga, J. Gefitinib — novel targeted approach to treating cancer.Nature Rev. Cancer4, 956–965 (2004).
Chaudry, M. A., Sales, K., Ruf, P., Lindhofer, H. & Winslet, M. C. EpCAM an immunotherapeutic target for gastrointestinal malignancy: current experience and future challenges.Br. J. Cancer96, 1013–1019 (2007).
Chatal, J. F. et al. Survival improvement in patients with medullary thyroid carcinoma who undergo pretargeted anti-carcinoembryonic-antigen radioimmunotherapy: a collaborative study with the French Endocrine Tumor Group.J. Clin. Oncol.24, 1705–1711 (2006).
Tolcher, A. W. et al. Phase I pharmacokinetic and biologic correlative study of mapatumumab, a fully human monoclonal antibody with agonist activity to tumor necrosis factor-related apoptosis-inducing ligand receptor-1.J. Clin. Oncol.25, 1390–1395 (2007).
Hudziak, R. M. et al. p185HER2 monoclonal antibody has antiproliferative effectsin vitro and sensitizes human breast tumor cells to tumor necrosis factor.Mol. Cell Biol.9, 1165–1172 (1989).
Crowe, J. S., Hall, V. S., Smith, M. A., Cooper, H. J. & Tite, J. P. Humanized monoclonal antibody CAMPATH-1H: myeloma cell expression of genomic constructs, nucleotide sequence of cDNA constructs and comparison of effector mechanisms of myeloma and Chinese hamster ovary cell-derived material.Clin. Exp. Immunol.87, 105–110 (1992).
Prewett, M. et al. The biologic effects of C225, a chimeric monoclonal antibody to the EGFR, on human prostate carcinoma.J. Immunother. Emphasis Tumor Immunol.19, 419–427 (1996).
Hurwitz, H. et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.N. Engl. J. Med.350, 2335–2342 (2004).
Pastan, I., Hassan, R., FitzGerald, D. J. & Kreitman, R. J. Immunotoxin therapy of cancer.Nature Rev. Cancer6, 559–565 (2006).
Pennell, C. A. & Erickson, H. A. Designing immunotoxins for cancer therapy.Immunol. Res.25, 177–191 (2002).
Khawli, L. A., Hu, P. & Epstein, A. L. Cytokine, chemokine, and co-stimulatory fusion proteins for the immunotherapy of solid tumors.Handb. Exp. Pharmacol.181, 291–328 (2008).
Goldenberg, D. M. & Sharkey, R. M. Novel radiolabeled antibody conjugates.Oncogene26, 3734–3744 (2007).
von Mehren, M., Adams, G. P. & Weiner, L. M. Monoclonal antibody therapy for cancer.Annu. Rev. Med.54, 343–369 (2003).
Bross, P. F. et al. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia.Clin. Cancer Res.7, 1490–1496 (2001).
Sievers, E. L. & Linenberger, M. Mylotarg: antibody-targeted chemotherapy comes of age.Curr. Opin. Oncol.13, 522–527 (2001).
Arons, E. et al. Characterization of T-cell repertoire in hairy cell leukemia patients before and after recombinant immunotoxin BL22 therapy.Cancer Immunol. Immunother.55, 1100–1110 (2006).
Mandler, R., Kobayashi, H., Hinson, E. R., Brechbiel, M. W. & Waldmann, T. A. Herceptin–geldanamycin immunoconjugates: pharmacokinetics, biodistribution, and enhanced antitumor activity.Cancer Res.64, 1460–1467 (2004).
Seidman, A. et al. Cardiac dysfunction in the trastuzumab clinical trials experience.J. Clin. Oncol.20, 1215–1221 (2002).
Byrd, J. C. et al. Rituximab therapy in hematologic malignancy patients with circulating blood tumor cells: association with increased infusion-related side effects and rapid blood tumor clearance.J. Clin. Oncol.17, 791–795 (1999).
Piccart-Gebhart, M. J. et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer.N. Engl. J. Med.353, 1659–1672 (2005).
Zee-Cheng, R. K. & Cheng, C. C. Screening and evaluation of anticancer agents.Methods Find. Exp. Clin. Pharmacol.10, 67–101 (1988).
Issell, B. F. & Crooke, S. T. Maytansine.Cancer Treat. Rev.5, 199–207 (1978).
Zhou, X. J. & Rahmani, R. Preclinical and clinical pharmacology of vinca alkaloids.Drugs44 (Suppl 4), 1–16 (1992).
Cores, E. P., Holland, J. F., Wang, J. J. & Sinks, L. F. Doxorubicin in disseminated osteosarcoma.JAMA221, 1132–1138 (1972).
Johnson, I. S., Armstrong, J. G., Gorman, M. & Burnett, J. P. Jr. The vinca alkaloids: a new class of oncolytic agents.Cancer Res.23, 1390–1427 (1963).
Rowinsky, E. K. & Donehower, R. C. The clinical pharmacology and use of antimicrotubule agents in cancer chemotherapeutics.Pharmacol. Ther.52, 35–84 (1991).
Uppuluri, S., Knipling, L., Sackett, D. L. & Wolff, J. Localization of the colchicine-binding site of tubulin.Proc. Natl Acad. Sci. USA90, 11598–11602 (1993).
Damayanthi, Y. & Lown, J. W. Podophyllotoxins: current status and recent developments.Curr. Med. Chem.5, 205–252 (1998).
Wani, M. C., Taylor, H. L., Wall, M. E., Coggon, P. & McPhail, A. T. Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent fromTaxus brevifolia.J. Am. Chem. Soc.93, 2325–2327 (1971).
Fuchs, D. A. & Johnson, R. K. Cytologic evidence that taxol, an antineoplastic agent fromTaxus brevifolia, acts as a mitotic spindle poison.Cancer Treat. Rep.62, 1219–1222 (1978).
Giannakakou, P. et al. A common pharmacophore for epothilone and taxanes: molecular basis for drug resistance conferred by tubulin mutations in human cancer cells.Proc. Natl Acad. Sci. USA97, 2904–2909 (2000).
Ehrlich, P. Über den jetzigen Stand der Chemotherapie.Berichte der Deutschen Chemischen Gesellschaft42, 17–47 (1909) (in German).
Panthananickal, A., Hansch, C. & Leo, A. Structure–activity relationship of aniline mustards acting against B-16 melanoma in mice.J. Med. Chem.22, 1267–1269 (1979).
Hansch, C., Hoekman, D. & Gao, H. Comparative QSAR: toward a deeper understanding of chemicobiological interactions.Chem. Rev.96, 1045–1076 (1996).
Dolle, R. E. Comprehensive survey of combinatorial library synthesis: 1999.J. Comb. Chem.2, 383–433 (2000).
Thomas, R. K. et al. High-throughput oncogene mutation profiling in human cancer.Nature Genet.39, 347–351 (2007).
Thomas, R. K. et al. Sensitive mutation detection in heterogeneous cancer specimens by massively parallel picoliter reactor sequencing.Nature Med.12, 852–855 (2006).
Weir, B. A. et al. Characterizing the cancer genome in lung adenocarcinoma.Nature450, 893–898 (2007).
Haney, S. A. Expanding the repertoire of RNA interference screens for developing new anticancer drug targets.Expert Opin. Ther. Targets.11, 1429–1441 (2007).
Konig, R. et al. A probability-based approach for the analysis of large-scale RNAi screens.Nature Meth.4, 847–849 (2007).
Delucas, L. J. et al. Protein crystallization: virtual screening and optimization.Prog. Biophys. Mol. Biol.88, 285–309 (2005).
Sarver, R. W. et al. Binding thermodynamics of substituted diaminopyrimidine renin inhibitors.Anal. Biochem.360, 30–40 (2007).
Sharp, S. Y. et al. Inhibition of the heat shock protein 90 molecular chaperonein vitro andin vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues.Mol. Cancer Ther.6, 1198–1211 (2007).
Oltersdorf, T. et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours.Nature435, 677–681 (2005).
Wang, J. & Ramnarayan, K. Toward designing drug-like libraries: a novel computational approach for prediction of drug feasibility of compounds.J. Comb. Chem.1, 524–533 (1999).
Schneider, G. & Fechner, U. Computer-basedde novo design of drug-like molecules.Nature Rev. Drug Discov.4, 649–663 (2005).
Yang, J., Shamji, A., Matchacheep, S. & Schreiber, S. L. Identification of a small-molecule inhibitor of class Ia PI3Ks with cell-based screening.Chem. Biol.14, 371–377 (2007).
Druker, B. J. et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia.N. Engl. J. Med.355, 2408–2417 (2006).
Motzer, R. J. et al. Sunitinib versus interferon α in metastatic renal-cell carcinoma.N. Engl. J. Med.356, 115–124 (2007).
Smith, I. E. Trastuzumab for early breast cancer.Lancet367, 107 (2006).
Barnett, D., Stevens, A. & Longson, C. Appraisal of bevacizumab and cetuximab for treatment of metastatic colorectal cancer in the UK.Lancet Oncol.7, 807–808 (2006).
Escudier, B. et al. Sorafenib in advanced clear-cell renal-cell carcinoma.N. Engl. J. Med.356, 125–134 (2007).
Mayer, E. L., Lin, N. U. & Burstein, H. J. Novel approaches to advanced breast cancer: bevacizumab and lapatinib.J. Natl Compr. Cancer Netw.5, 314–323 (2007).
Richon, V. M. et al. A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases.Proc. Natl Acad. Sci. USA95, 3003–3007 (1998).
Stebbins, C. E. et al. Crystal structure of an Hsp90–geldanamycin complex: targeting of a protein chaperone by an antitumor agent.Cell89, 239–250 (1997).
Hodgson, J. ADMET--turning chemicals into drugs.Nature Biotechnol.19, 722–726 (2001).
Finnin, M. S. et al. StructuRes. of a histone deacetylase homologue bound to the TSA and SAHA inhibitors.Nature401, 188–193 (1999).
Kerkela, R. et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate.Nature Med.12, 908–916 (2006).
Strebhardt, K. & Ullrich, A. Another look at imatinib mesylate.N. Engl. J. Med.355, 2481–2482 (2006).
Chu, T. F. et al. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib.Lancet370, 2011–2019 (2007).
Daub, H., Specht, K. & Ullrich, A. Strategies to overcome resistance to targeted protein kinase inhibitors.Nature Rev. Drug Discov.3, 1001–1010 (2004).
Gorre, M. E. et al. Clinical resistance to STI-571 cancer therapy caused by BCR–ABL gene mutation or amplification.Science293, 876–880 (2001).
Shah, N. P. et al. Multiple BCR–ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia.Cancer Cell2, 117–125 (2002).
Azam, M., Latek, R. R. & Daley, G. Q. Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL.Cell112, 831–843 (2003).
Schindler, T. et al. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase.Science289, 1938–1942 (2000).
Liu, Y. & Gray, N. S. Rational design of inhibitors that bind to inactive kinase conformations.Nature Chem. Biol.2, 358–364 (2006).
Levinson, N. M. et al. A Src-like inactive conformation in the abl tyrosine kinase domain.PLoS Biol.4, e144 (2006).
Guilhot, F. et al. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase.Blood109, 4143–4150 (2007).
Lombardo, L. J. et al. Discovery ofN-(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 (2004).
Weisberg, E. et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr–Abl.Cancer Cell7, 129–141 (2005).
Lynch, T. J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.N. Engl. J. Med.350, 2129–2139 (2004).
Kola, I. & Landis, J. Can the pharmaceutical industry reduce attrition rates?Nature Rev. Drug Discov.3, 711–715 (2004).
Becher, O. J. & Holland, E. C. Genetically engineered models have advantages over xenografts for preclinical studies.Cancer Res.66, 3355–3358, discussion 3358–3359 (2006).
Sharpless, N. E. & DePinho, R. A. The mighty mouse: genetically engineered mouse models in cancer drug development.Nature Rev. Drug Discov.5, 741–754 (2006).
Frese, K. K. & Tuveson, D. A. Maximizing mouse cancer models.Nature Rev. Cancer7, 645–658 (2007).
Ludwig, J. A. & Weinstein, J. N. Biomarkers in cancer staging, prognosis and treatment selection.Nature Rev. Cancer5, 845–856 (2005).
Hofstra, R. M. et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma.Nature367, 375–376 (1994).
Morris, S. W. et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma.Science263, 1281–1284 (1994).
Wilhelm, S. M. et al. BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF–MEK–ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis.Cancer Res.64, 7099–7109 (2004).
Carlomagno, F. et al. BAY 43–9006 inhibition of oncogenic RET mutants.J. Natl Cancer Inst.98, 326–334 (2006).
Godl, K. et al. An efficient proteomics method to identify the cellular targets of protein kinase inhibitors.Proc. Natl Acad. Sci. USA100, 15434–15439 (2003).
Rual, J. F. et al. Towards a proteome-scale map of the human protein–protein interaction network.Nature437, 1173–1178 (2005).
Espina, V., Wulfkuhle, J. D., Calvert, V. S., Petricoin, E. F. III & Liotta, L. A. Reverse phase protein microarrays for monitoring biological responses.Methods Mol. Biol.383, 321–336 (2007).
Balch, W. E., Morimoto, R. I., Dillin, A. & Kelly, J. W. Adapting proteostasis for disease intervention.Science319, 916–919 (2008).
Buchdunger, E. et al. Selective inhibition of the platelet-derived growth factor signal transduction pathway by a protein-tyrosine kinase inhibitor of the 2-phenylaminopyrimidine class.Proc. Natl Acad. Sci. USA92, 2558–2562 (1995).
Buchdunger, E. et al. Inhibition of the Abl protein-tyrosine kinasein vitro andin vivo by a 2-phenylaminopyrimidine derivative.Cancer Res.56, 100–104 (1996).
Zimmermann, J. et al. Phenylamino-pyrimidine (PAP) derivatives: a new class of potent and selective inhibitors of protein kinase C (PKC).Arch. Pharm. (Weinheim)329, 371–376 (1996).
Coussens, L. et al. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene.Science230, 1132–1139 (1985).
Ullrich, A. et al. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells.Nature309, 418–425 (1984).
Acknowledgements
We thank S. Kappel for establishing the list of references. This work was supported by grants from the Deutsche Krebshilfe, Messer Stiftung, Sander Stiftung, Schleussner Stiftung, Else Kröner-Fresenius/Carls-Stiftung and the Dresdner Bank.
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Klaus Strebhardt is at the Department of Obstetrics and Gynaecology, School of Medicine, J.W. Goethe-University, Theodour-Stern-Kai 7, 60590 Frankfurt, Germany.,
Klaus Strebhardt
Axel Ullrich is at the Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Am Klopferspitz 18A, 82152 Martinsried, Germany.,
Axel Ullrich
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- Axel Ullrich
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Correspondence toKlaus Strebhardt.
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anaplastic large-cell lymphoma
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Strebhardt, K., Ullrich, A. Paul Ehrlich's magic bullet concept: 100 years of progress.Nat Rev Cancer8, 473–480 (2008). https://doi.org/10.1038/nrc2394
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