Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug

Key Points

  • Chronic myelogenous leukaemia (CML) is a clonal haematological disorder that is characterized by a reciprocal translocation between chromosomes 9 and 22, and provided the first evidence of a specific genetic change associated with human cancer.

  • The molecular consequence of this interchromosomal exchange is the creation of the BCR–ABL gene, which encodes a protein with elevated tyrosine-kinase activity. The demonstration that the creation of BCR–ABL is the molecular pathogenic event in CML provided the first potential drug target that clearly differed in its activity between normal and leukaemic cells.

  • Importantly, BCR–ABL could be approached with classical tools of pharmacology, as its activity could clearly be described and measured in biochemical as well as cellular assays. Furthermore, cell lines derived from human leukaemic cells with the same chromosomal abnormality were available.

  • A lead compound identified in a screen for inhibitors of protein kinase C was optimized to give a methyl-piperazine derivative that was originally named STI571 (imatinib, now known as Glivec or Gleevec), which was selected as the most promising candidate for clinical development.

  • In in vitro screens against a panel of protein kinases, Glivec was found to inhibit the autophosphorylation of essentially three kinases: BCR–ABL, c-KIT and the platelet-derived growth factor (PDGF) receptor.

  • Promising in vivo results — for example, with BCRABL-transformed cells in syngeneic mice — coupled with the facts that CML is essentially caused by a single molecular defect and that responses in CML can be measured easily using blood leukocyte count as the end point, led to CML being selected as the first indication for Phase I clinical testing of Glivec.

  • The clinical development of Glivec was extremely rapid; the first patient was treated in June 1998, and less than three years later, on the basis of three large, multinational trials that showed Glivec to be safe and effective in all stages of CML, Glivec was approved by the FDA in May 2001. European and Japanese approval followed in November 2001.

  • Current studies are investigating the activity of Glivec in cancers in which c-KIT and PDGF receptors might represent promising therapeutic targets. For example, gastrointestinal stromal tumours (GIST) are characterized by gain-of-function mutations in the KIT gene, and in February 2002, Glivec was approved by the FDA for the treatment of GIST.

Abstract

In the early 1980s, it became apparent that the work of pioneers such as Robert Weinberg, Mariano Barbacid and many others in identifying cancer-causing genes in humans was opening the door to a new era in anticancer research. Motivated by this, and by dissatisfaction with the limited efficacy and tolerability of available anticancer modalities, a drug discovery programme was initiated with the aim of rationally developing targeted anticancer therapies. Here, we describe how this programme led to the discovery and continuing development of Glivec (Gleevec in the United States), the first selective tyrosine-kinase inhibitor to be approved for the treatment of a cancer.

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Figure 1: Summary of the chemical optimization.
Figure 2
Figure 3: Dose–response relationship of Glivec in CML (Phase I study).
Figure 4: Haematological and cytogenetic response in CML: Phase II data.
Figure 5: Key points in the discovery and development of Glivec.

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Acknowledgements

We would like to thank the members of the Glivec International Project Team for their crucial contribution to the success of this programme and their kind review of this manuscript: P. Boultbee, V. Buss, S. Dimitrijevic, A. Dortok, D. Filipovic, I. Gathmann, H. Godman, J. Jaffe, L. Letvak, P. Marbach, R. Miranda, J. Ogorka, C. Ogawa, B. Peng, S. Silberman, F. Sutter, S. Szabo, S. Wells and J. M. Ford. We also thank B. Druker for his crucial input and a fruitful collaboration throughout this programme, and N. Lydon for his contribution in the early phase of the programme. We thank also C. Schmid for her assistance in editing the manuscript.

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Correspondence to Renaud Capdeville.

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DATABASES

Cancer.gov

acute lymphoblastic leukaemia

acute myelogenous leukaemia

chronic myelogenous leukaemia

ovarian cancer

prostate cancer

small-cell lung cancer

testicular cancer

LocusLink

ABL

Abl

AGP

AKT

albumin

ARG kinase

ATP5A1

ATP5C1

BAK1

BCL-XL

BCR

Bcr

bFGF

Bruton tyrosine kinase

COL1A1

CRKL

EGF receptor

c-ERBB2

ERK1

ERK2

FGF

c-FMS

v-fms

IGF-1 receptor

INK4B

insulin receptor

JAK2

c-KIT

p27

PDGF-α

PDGF-β

PDGFR-α

PDGFR-β

P-GP

PKC

SCF

v-SRC

STAT5

TEL

VEGF

Medscape DrugInfo

cytarabine

Glivec

interferon

taxol

verapamil

FURTHER INFORMATION

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Glossary

LEUKAEMIA

Leukaemia is an uncontrolled proliferation of one type of white blood cell (leukocyte).

APOPTOSIS

Programmed cell death.

SYNGENEIC MODEL

An animal model in which the injected tumour cells are derived from the same animal species as the host animal.

GRADE III–IV ADVERSE EVENTS

For each adverse event that is associated with a specific treatment, grades are assigned and defined using a scale from 0 to V. Grade III, severe and undesirable adverse event; grade IV, life-threatening or disabling adverse event.

AUTOCRINE

Describes an agent secreted from a cell that acts on the cell in which it is produced.

PARACRINE

Describes an agent secreted from a cell that acts on other cells in the local environment.

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Capdeville, R., Buchdunger, E., Zimmermann, J. et al. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat Rev Drug Discov 1, 493–502 (2002). https://doi.org/10.1038/nrd839

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