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Tyrosine kinases as targets in cancer therapy - successes and failures
1Novartis Pharma AG, Oncology Research, CH4002 Basel, Switzerland. peter.traxler@pharma.novartis.com
Abstract:
Protein kinases play a crucial role in signal transduction and also in cellular proliferation, differentiation and various regulatory mechanisms. The inhibition of growth-related kinases, especially tyrosine kinases, might therefore provide new therapies for diseases such as cancer. Due to the enormous progress that has been made in the past few years in the identification of the human genome, in molecular and cell biology technologies, in structural biology and in bioinformatics, the number of receptor and non-receptor tyrosine kinases that have been identified as valuable molecular targets has greatly increased. Currently, more than 20 different tyrosine kinase targets are under evaluation in drug discovery projects in oncology. The progress made in the crystallisation of protein kinases, in most cases complexed with ATP-site-directed inhibitors, has confirmed that the ATPbinding domain of tyrosine kinases is an attractive target for rational drug design; more than 20 ATP-competitive, low molecular weight inhibitors are in various phases of clinical evaluation. Meanwhile, clinical proof-of-concept (POC) has been achieved with several antibodies and small molecules targeted against tyrosine kinases. With Herceptin, Glivec and Iressa (registered in Japan), the first kinase drugs have entered the market. This review describes the preclinical and clinical status of low molecular weight drugs targeted against different tyrosine kinases (e.g., epidermal growth factor receptor [EGFR], vascular endothelial growth factor receptor [VEGFR], platelet-derived growth factor receptor [PDGFR], Kit, Fms-like tyrosine kinase [Flt]-3), briefly describes new targets, and provides a critical analysis of the current situation in the area of tyrosine kinase inhibitors.
Insights
Targeting tyrosine kinases, crucial for cell growth, offers new cancer therapies. Several drugs inhibiting these kinases are now approved, with many more in development for oncology.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Protein kinases regulate vital cellular processes including proliferation and differentiation.
- Inhibiting growth-related kinases, particularly tyrosine kinases, presents a promising therapeutic strategy for cancer.
- Advances in genomics, molecular biology, structural biology, and bioinformatics have identified numerous tyrosine kinase targets.
Purpose of the Study:
- To review the preclinical and clinical status of low molecular weight drugs targeting tyrosine kinases.
- To highlight new tyrosine kinase targets in drug discovery.
- To critically analyze the current landscape of tyrosine kinase inhibitors in oncology.
Main Methods:
- Review of preclinical and clinical data for tyrosine kinase inhibitors.
- Analysis of drug discovery projects targeting receptor and non-receptor tyrosine kinases.
- Examination of structural biology data for ATP-binding domain-directed inhibitors.
Main Results:
- Over 20 tyrosine kinase targets are under investigation in oncology drug discovery.
- More than 20 ATP-competitive inhibitors are in clinical evaluation.
- Clinical proof-of-concept established for antibodies and small molecules targeting tyrosine kinases.
- Market approval for initial kinase inhibitors like Herceptin, Glivec, and Iressa.
Conclusions:
- The ATP-binding domain of tyrosine kinases is a validated target for rational drug design.
- Tyrosine kinase inhibitors represent a significant advancement in cancer therapy.
- Ongoing research continues to identify new targets and develop novel inhibitors for various tyrosine kinases.