The Glivec (imatinib) story begins with 2 Philadelphia researchers: Peter Nowell, MD, of the University of Pennsylvania School of Medicine, and David Hungerford, MD, of the Institute for Cancer Research. They were able to identify a genetic mutation in patients with CML (chronic myeloid leukaemia) in 1960.(1) The 2 researchers found that a section of DNA was missing from chromosome 22. This alteration soon became known as the Philadelphia (Ph) chromosome and could be detected in approximately 95% of patients with CML. The discovery meant that for the first time ever, scientists had discovered a genetic abnormality linked to a specific kind of cancer. The discovery of the link between the Ph chromosome and CML set off an explosion of research into the genetic causes of cancer.

The Great Shift

The next significant advance in the understanding of CML took place 13 years later through the work of Janet Rowley, MD, and researchers at the University of Chicago. They realised that the missing section of DNA from chromosome 22 (which characterised CML) had shifted to chromosome 9, a phenomenon known as "translocation."(2) The recognition of this phenomenon paved the way for many later researchers, who have since been able to match dozens of translocations to various cancers. (In 1998, Nowell and Rowley received the Albert Lasker Medical Research Award, which is sometimes called the "American Nobel Prize", for their work in CML.)

The remainder of the 1970s saw only incremental progress in genetic cancer research. However, in the 1980s, 2 researchers from the California Institute of Technology, David Baltimore, PhD, and Owen N. Witte, MD, identified the principal cause of CML. The Ph chromosome produces an enzyme that plays a central role in aberrant cell growth and division. The enzyme, a fusion protein (Bcr-Abl) that enhances tyrosine kinase activity, changes the cell's normal genetic instructions. This aberrant enzyme sends out signals through multiple pathways within the cell, resulting in the overproduction of white blood cells in the body. The result is that, while a healthy cubic millimetre of blood contains 4,000 to 10,000 white blood cells, blood from a patient with CML contains 10 to 25 times this amount.(3) The massive increase in the number of white blood cells characterises CML.

Glivec: Realising a Dream

With the groundbreaking discovery that a single enzyme could cause the development of CML, medical researchers faced a rare opportunity. Unlike previous efforts, the genetic target was clear, and the development of a drug that could block Bcr-Abl could proceed rationally. Work soon began in early 1990 on the discovery of Bcr-Abl inhibitors by researchers at Novartis (then Ciba-Geigy).(4,5) The 2 lead researchers, Nicholas Lydon, PhD, and Alex Matter, MD, were particularly optimistic about one promising compound from a pool of several potential agents. However, it had only weak, non-specific activity against Bcr-Abl.

The task of improving this "promising compound" was assigned to 4 Novartis scientists, Drs. Juerg Zimmermann (Medicinal Chemistry), Elisabeth Buchdunger (Cell Biology), Helmut Mett (Screening and Enzymology), and Thomas Meyer (Enzymology). They soon began changing, adding, and deleting certain molecules to alter the original compound's activity against Bcr-Abl.

After 2 years of painstaking experimentation, the team finally transformed the original compound-a weak, non-specific inhibitor-into a potent, specific inhibitor of Bcr-Abl. This agent effectively blocked the enzyme that leads to the proliferation of white blood cells in patients with CML. Their pioneering work led to a class of compounds with optimised activity against Bcr-Abl and other kinases.(6) The result of this monumental achievement was the filing of the basic patent application covering this class of inhibitors in 1993 and 1995.

Building on the Dream

Building on the enormous experimental achievement of Drs. Zimmermann, Buchdunger, Mett, and Meyer, Novartis began a collaboration in 1994 with Brian Druker, MD, a haematologist and oncologist with an interest in tyrosine kinases and CML. Their work profiled the activity of 2 compounds in cellular models of CML. They found that one compound, which would eventually be known as Glivec, showed selective in vitro activity against the Bcr-Abl protein, and it suppressed the proliferation of Bcr-Abl-expressing cells in vitro and in vivo in one critical study. Of equal significance, the compound did not demonstrate significant activity against normal cells,(7) which immediately distinguished it from traditional cancer treatments. Other researchers subsequently confirmed these findings.(8,9)

Over the next several years, Novartis conducted the additional research needed to start clinical trials, including elaboration of the chemical synthesis, studies of drug formulation, pharmacokinetics, and toxicology screenings.

These studies led to the original reports on this class of inhibitor that were first published by Novartis scientists in 1996.(10-13) While the results from initial oral bioavailability and toxicology studies showed promise, additional refinements were needed. Therefore, pre-clinical development of Glivec soon began, with Lydon directing a multidisciplinary team of scientists. Matter, Lydon, Druker, Baltimore, and Witte would eventually be awarded the 2001 Warren Alpert Foundation Prize for their work with Bcr-Abl. This honour seeks to recognise the full breadth of the development of a therapy-the basic scientific underpinnings, pre-clinical exploration, and clinical trial investigations.

References

1. Nowell PC, Hungerford DA. A minute chromosome in human chronic granulocytic leukaemia. Science. 1960;132:164-172.
2. Rowley D. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973;243:290-293.
3. Mughal T, Goldman J. Understanding leukaemia and related cancers. Oxford: Blackwell Science Ltd. 1999.
4. Lydon NB, Adams B, Poschet JF, et al. An E. coli expression system for the rapid purification and characterization of a v-abl tyrosine protein kinase. Oncogene Research. 1990;5:161-173.
5. Geissler JF, Roesel JL, Meyer T, et al. Benzopyranones and benzothiopyranones: a class of tyrosine protein kinase inhibitors with selectivity for the v-abl kinase. Cancer Research. 1992;52:4492-4498.
6. Druker BJ, Lydon NB. Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukaemia. J Clin Invest. 2000;105:3-7.
7. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nature Med. 1996;2:561-566.
8. Deininger MW, Goldman JM, Lydon N, et al. The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood. 1997;90:3691-3698.
9. Gambacorti-Passerini C, le Coutre P, Mologni L, et al. Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis. Blood Cells Mol Dis. 1997;23:380-394.
10. Buchdunger E, Zimmermann J, Mett H, et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Research. 1996;56:100-104.
11. Zimmermann J, Caravtti G, Mett H, et al. Phenylamino-pyrimidine (PAP) derivatives: a new class of potent and highly selective PDGF-receptor autophosphorylation inhibitors. Bioorgan Med Chem Lett. 1996;6:1221-1226.
12. Zimmermann J, Buchdunger E, Mett H, et al. Potent and selective inhibitors of the ABL-kinase: phenylamino-pyrimidine (PAP) derivatives. Bioorgan Med Chem Lett. 1997;7:182-192.
13. Zimmermann J, Buchdunger E, Mett H, et al. Phenylamino-pyrimidine (PAP) derivatives: a new class of potent and selective inhibitors of protein kinase c (PKC). Arch Pharm. 1996;329:371-376.

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