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PHL 616
Drug Discovery & Development
Fifth Lecture
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
Creation of a new drug, Case histories
 Imatinib (Gleevec), contd.
 Tyrosine kinases are enzymes that transfer phosphate from ATP to tyrosine
residues on substrate proteins that in turn regulate cellular processes such
as proliferation, differentiation and survival
 Therefore, it is not surprising that deregulated tyrosine kinase activity has a
central role in malignant transformation. This has also made tyrosine
kinases attractive therapeutic targets for pharmacologic inhibition
 On this basis, the oncology team of Ciba-Geigy (later Novartis) began a
project seeking specific inhibitors of Abl kinase
 Imatinib (signal transduction inhibitor 571; STI571, formerly CGP57148B)
is a rationally designed abl-specific tyrosine kinase inhibitor
Creation of a new drug, Case histories
 Imatinib (Gleevec), contd.
 Ciba-Geigy team began a project seeking specific inhibitors of Abl kinase
by developing routine biochemical assays for Abl and other kinases
 Screening of synthetic compound libraries showed that compounds of the
2-phenylaminopyrimidine class showed selectivity in blocking Abl and
PDGF-receptor kinases
 Systematic chemical derivatization led to the synthesis of imatinib in 1992,
roughly 8 years after starting the project
 Imatinib had no major pharmacokinetic or toxicological shortcomings, and
was highly effective in suppressing the growth of cells engineered to
express Bcr-Abl, and of human tumor cells transplanted into mice
 Importantly, it also inhibited the growth in culture of peripheral blood or
bone marrow cells from CML patients
 This was valuable, as it is rarely possible to carry out such ex vivo tests
on material from patients – normally, it is necessary to wait until the
compound enters Phase II trials before any evidence relating to clinical
efficacy emerges
Creation of a new drug, Case histories
 Imatinib (Gleevec), contd.
 On that basis the project was given high priority & an accelerated clinical
trials program was devised. The first trials, beginning in 1998, were
performed not on normal subjects, but on 83 CML patients who had failed
to respond to treatment with interferon
 Different doses were tested in patients, and the pharmacokinetic
parameters, adverse effects and clinical response were measured in
parallel. The results showed an unequivocal clinical effect, with 100% of
patients receiving the higher doses showing a good hematological
response
 As a result, and because the regulatory procedures were dispatched
particularly rapidly, the drug was registered in record time, in May 2001,
just 3 years after being tested for the first time in humans
Creation of a new drug, Case histories
 Imatinib (Gleevec), contd.
 Why was the imatinib project successful?
1. The selection of a precisely defined molecular target which was known to
be disease relevant, and was amenable to modern assay technologies
2. Setting up the various kinase assays took 4–5 years, but thereafter
screening produced the lead series of compounds rather quickly. Imatinib
itself was made within 4 years of starting the screening program
3. Avoiding the pitfalls of pharmacokinetics and toxicology, which so often
hinder development, was very fortunate
4.
The speed of clinical development and registration was exceptional,
because CML is resistant to conventional anticancer drugs, and so
imatinib did not have to be compared with other treatments
5.
The designation of imatinib as an ‘orphan drug’, based on the rarity
of CML, allowed the trials program to be simplified and accelerated
6.
Its action is readily monitored by hematological tests, permitting a
rapid clinical readout. The therapeutic effect of the drug on
circulating white cells is directly related to its plasma level, which is
often not the case for drugs acting on solid tumors
Creation of a new drug, Case histories
 Trastuzumab (Herceptin)
 Trastuzumab is a humanized murine monoclonal antibody that binds
specifically to the extracellular domain of the human epidermal growth
factor (EGF) receptor 2 (HER2) protein
 The EGF family of receptor tyrosine kinases comprises four members:
1.
HER1 (EGFR/ErbB1)
2.
HER2 (neu/ErbB2)
3.
HER3 (ErbB3)
4.
HER4 (ErbB4)
 The Her2 receptor was first cloned in 1985, and 2 years later it was found
to be strongly over-expressed in the most aggressive breast cancers
 HER2 is a key contributor to normal cell growth and differentiation. However,
when overexpressed, it is associated with neoplastic transformation of cells
 Approximately 15% to 20% of breast cancers show HER2 overexpression
 HER2-positive malignancies have a significantly more aggressive disease
course and lead to a worse clinical outcome, including shortened overall
survival, compared with those that do not overexpress HER2
Kinase-linked Receptors,
Conformation
change
Dimerisation
A
Growth Factor Receptors
Tyrosine
Phosphorylation
autophosphrylation
of Grb2
Activation of Ras
GDP/GTP Exchange
MEMBRANE
Ras
Grb2
+
Sos
Tyrosine
residue
GTP
Activation
Raf
Grb2
Mek
Binding of SH2-domain
protein (Grb2)
 Agonist binding leads to dimerisation and autophosphorylation of the
intracellular domain of each receptor
 SH2 domain proteins, Grb2, then bind to the phosphorylated receptor and
are themselves phosphorylated
 Ras, which is a proto-oncogene product, functions like a G-protein, and
conveys the signal (by GDP/GTP exchange)
 Activation of Ras in turn activates Raf, which is the first of a sequence of
three kinases, each of which phosphorylates, and activates, the next in line
 The last of these, mitogen-activated protein (MAP) kinase, phosphorylates
one or more transcription factors that initiate gene expression, resulting in a
variety of cellular responses, including cell division
MAP kinase
Various transcription
factors
NUCLEUS
Gene Transcription
Creation of a new drug, Case histories
 Trastuzumab (Herceptin)
 Trastuzumab is a humanized murine monoclonal antibody that binds
specifically to the extracellular domain of the human epidermal growth
factor (EGF) receptor 2 (HER2) protein
Creation of a new drug, Trastuzumab
Creation of a new drug, Case histories
 Trastuzumab (Herceptin), contd.
 This project, which took 8 years from compound discovery to registration,
shows the speed with which biopharmaceuticals, under the right
conditions, can be developed
 Genentech used its in-house technology to develop a humanized mouse
monoclonal antibody that blocked the function of the receptor and
suppressed the proliferation of receptor-bearing cells
 Compared with conventional lead finding and lead optimization of
synthetic molecules, this took very little time – only 2 years from the start
of the project
 Antibodies generally exhibit much simpler and more predictable
pharmacological effects than synthetic compounds, and run into fewer
problems with chemical development, formulation and toxicology, so that
trastuzumab was able to enter Phase I within 2 years
 Clear-cut efficacy was evident in Phase II, and the rest of the clinical
development was rapid and straightforward
 Given the right circumstances, biopharmaceuticals can be developed
more quickly and more cheaply than conventional drugs
Creation of a new drug, Wrap up