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Printable Handouts
Navigable Slide Index
- Introduction
- Protein tyrosine kinases (TKs)
- Phosphorylation of tyrosine residues
- Two classes of TKs
- Nonreceptor TKs
- Receptor TKs (1)
- Receptor and nonreceptor TKs
- Receptor TKs (2)
- Activation of receptor TKs
- The effects of rTK activation
- Mechanisms of TK dysregulation in cancer
- Consequences of TK activation in cancer
- Strategies to target TKs in cancer therapy
- CML- a model disease for science advancement
- Chronic myeloid leukaemia (CML)
- 1960 - discovery of the Philadelphia chromosome
- 1973 - the first description of human oncogene
- 1990- BCR-ABL causes CML in mice
- Imatinib specifically targets BCR-ABL oncogene
- Imatinib mesylate (1)
- Imatinib mesylate (2)
- Imatinib- the IRIS trial
- Targeting other rTKs
- rTK dysregulation in cancer
- Mutations in rTKs lead to constitutive activation
- Epidermal growth factor receptor (EGFR)
- Small molecule inhibitors of EGFR
- Factors predicting response to EGFR TK inhibitors
- Cetuximab
- Her-2/neu
- Herceptin
- C-KIT
- PDGFR
- Sites of KIT and PDGFR alpha mutations in GIST
- Treatment paradigms for the treatment of GIST
- Imatinib targets in solid tumours
- FLT3: a major target in AML
- Direct inhibitors of FLT3
- C-MET
- Small-molecule MET inhibitors
- Vascular endothelial growth factor (receptor)
- Completed anti-VEGF therapy phase III trials
- Bevacizumab
- Fibroblast growth factor receptor 3 (FGFR 3)
- Other TK targets in hematologic malignancies
- Simultaneous inhibition of two TKs
- Vandetanib (ZD6474) and AZD2171
- Multitargeted TKIs: sunitinib malate
- Biological effects of sunitinib
- Properties of sunitinib malate
- Multitargeted TKIs: sorafenib
- Limitations of TK therapy: toxicity
- The unexpected cardiotoxicity of imatinib
- Limitations of TK therapy: resistance
- Limitations of TK therapy: resistance to mAbs
- Problems with imatinib
- Mechanisms of resistance to TKI therapy
- The development of resistance to imatinib
- Imatinib-resistant mutations in BCR-ABL
- Resistance mechanism
- T315I - "the mutation from hell"
- BMS-354825 (dasatinib)
- Imatinib resistant CML cells
- Overcoming resistance
- Identifying new targets
- The drug development process for TKIs
- Targeted therapy in haematological malignancies
- Targeted therapy in solid tumours
- Summary
Topics Covered
- Overview of tyrosine kinases
- Tyrosine kinase dysregulation in cancer
- The example of chronic myelogenous leukemia
- Receptor tyrosine kinases: function and involvement in cancer, treatment with small molecule inhibitors to these tyrosine kinases
- Inhibition of several tyrosine kinases
- Toxicity
- Resistance
- The future of treatment with tyrosine kinase inhibitors
Links
Series:
Categories:
Therapeutic Areas:
Talk Citation
Krause, D. (2022, April 12). Small molecule inhibitors of receptor tyrosine kinases [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved November 2, 2024, from https://doi.org/10.69645/BZAL9448.Export Citation (RIS)
Publication History
Financial Disclosures
- Dr. Daniela Krause has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
A selection of talks on Clinical Practice
Transcript
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0:00
My name is Daniela Krause from
Massachusetts General Hospital in Boston,
and I'm going to talk about small molecule
inhibitors of receptor tyrosine kinases.
Since the arrival of imatinib up for the
treatment of chronic myelogenous leukemia
in 2001 the use of other small
molecule inhibitors of tyrosine
kinases has experienced increasing
popularity over the last few years.
This really is the great story of the
successful translation of findings from
basic research to clinical medicine, but
also poses the question about
the future of modern medicine.
0:34
Tyrosine kinases belong to large group
of protein kinases they're enzymes that
can transfer a phosphate group from ATP
to a tyrosine residue in a protein.
The human genome contains
90 tyrosine kinases and
43 tyrosine kinase like genes,
they regulate cellular proliferation,
survival, differentiation,
function and motility.
They have largely been ignored for the
last 25 years in drug development because
of paucity of evidence for
a causative role in human cancer and
concerns about drug specificity and
toxicity.
But since the arrival of imatinib,
it was realized that tyrosine kinase
inhibitors can be used in specific cancers
in which a mutation that causes certain
tyrosine kinasaes to be
constitutively active.
1:21
Tyrosine kinases catalyze the transfer of
phosphate, as you can see on the top left
from ATP onto tyrosine residues, as you
can see on the top right onto proteins.
1:33
Two classes of tyrosine kinases exist.
Receptor tyrosine kinases and
non-receptor tyrosine kinases.
Nonreceptor tyrosine kinases
lack transmembrane domains, and