Target Proteins

Many of the early “simple” anti-cancer drugs used in chemotherapy, worked by intercalating between DNA base pairs thereby inhibiting growth and often resulting in cell toxicity (apoptosis). Inevitably, such molecules have wide-ranging side-effects and general toxicity. While death of cancer cells is a strategic goal, it would be obviously be valuable to selectively target cancer cells. Virtual Screening, computationally evaluates the potential of molecules to inhibit the normal functions of proteins and in the this project the following have been identified for the first phase of the project:

Superoxide dismutase (SOD)
Superoxide dismutase (SOD) is an enzyme that removes the superoxide (O2-) radical. We hear a lot in nutritional news about "antioxidants". Think of SOD as a natural antioxidant. Since cancer cells produce more oxidants than normal cells, they can basically oxidize themselves to death. That is why SOD is a target protein — if SOD is inhibited in the cancer cell, the cancer cells are damaged, controlling growth. (PDB reference - 1isa)

Vascular Endothelial Growth Factor (VEGF)
Vascular Endothelial Growth Factor (VEGF) stimulates the growth of blood vessels. The uncontrolled growth of cancer cells is legendary. But this sort of growth requires a lot of blood flow to the cell area. If the blood vessel growth can be restrained, then, in theory, so can cancer growth. (PDB reference - 1FLT – growth factor)

RAS proteins
RAS proteins give a chemical "message" that activate cell growth. Without this signaling factor, the cell doesn't "know" to grow. Inhibiting RAS in cancer cells means an end to their uncontrolled growth. (PDB reference - 821P)

Insulin Tyrosine Kinase. (IGF)
This is a representative of the many kinases which play key roles in facilitating growth of cancer cells. (PDB reference - 1GF1)

Cyclooxygenase (COX-2)
Cyclooxygenase (COX-2) keeps blood vessels open and flowing in areas where there is tissue damage or swelling that often occurs around certain cancerous growths. Again, by cutting off the necessary blood supply by inhibiting the COX, the cancerous cells may not survive.(PDB reference - COX-2) (J Med Chem (2000) 43 3168-3185.

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)

Fibroblast Growth Factor Receptor (1AGW)
Inhibition of which may reduce the growth of some cancer tumours by reducing the blood supply. (PDB reference - 1AGW)

CDK-2 (1AQ1)
Plays an important role in cell cycle regulation. (PDB reference - 1AQ1)

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)

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)