Essential enzymes that remove the superoxide (O2-) radical. Inhibition of such enzymes result in cell damage by free radicals and ultimately cell death. The high levels of O2- in certain cancers (such as leukaemia cells) provide an unusual mechanism for treatment by inhibiting SOD.
Vascular Endothelial Growth Factor (VEGF)
Mediates a critical stage in the development of cancer - the growth of blood vessels. In principle, inhibitors can be found for VEGF or the corresponding series of receptors, VEGFr-1 (also known as FLT-1) and VEGFr-2 (also known as KDR).
RAS proteins
Play a central role in cell growth (for which there appears to be no significant alternative signalling) It is conceivable that many of the inhibitors of H-RAS (for which there are crystal structures) will also inhibit N-RAS and K-RAS. In addition, there are crystal structures for Farnesyl Protein Transerase (FPT) which “activates” RAS and is consequently an alternative target.
Protein Tyrosine Kinases (PTK)
Play a fundamental role in signal transduction pathways and deregulation of this activity is common in many cancers. The structure of Insulin receptor tyrosine kinase was one of the first known and is a potential target of unknown selectivity.
Cyclo-oxygenase II (6COX)
A potent inhibitor should block prostaglandins production in inflamatory cells" (J Med Chem (2000) 43 3168-3185.
BCR-ABL a tyrosine kinase (1IEP)
Believed to be causally involved with chronic myeloid leukemia - see Science (2001) 292 p 399-400
RAF (1C1Y)
RAF interacts with activated RAS to signal cell growth. (PDB reference - 1C1Y)
Farnesyltransferase (1D8D)
Farnesyltransferase is responsible for activating RAS. (PDB reference - 1D8D)
Protein-Tyrosine-Phosphatase 1B (1BZH)
This is one of the protein tyrosine phosphatases which play a role in regulating cellular events. It is conceivable that inhibition of this protein will enable apoptosis (death of cancer cells). (PDB reference - 1BZH)
C-ABL Tyrosine Kinase
This is a mutant protein commonly expressed in chronic leukemia. It has been suggested that inhibition of the protein can not only prevent the development of Leukemia but shrink certain tumours – see Science 292 p399-400 (2001) (PDB reference - 1IEP)
CDK-2 (1AQ1)
Plays an important role in cell cycle regulation. (PDB reference - 1AQ1)
Fibrobalst Growth Factor Receptor (1AGW)
Inhibition of which may reduce the growth of some cancer tumours by reducing the blood supply. (PDB reference - 1AGW)
VEGFr1 (1FLT)
This is one of the receptors with which VEGF interacts and its inhibition (analogous to inhibiting VEGF itself) would prevent the development of blood vessels. (PDB reference - 1FLT)
The Protective Antigen
The so-called “protective antigen,” is one of the three proteins found in the anthrax toxin. The protective antigen binds with another protein, the lethal factor. This binding process is what allows cells to become toxic. By inhibiting the binding process, the resulting disease is prevented.
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