The 3-dimensional Structure Of Anticancer Drug-DNA Complexes Determined By X-ray Crystallography
Funder
National Health and Medical Research Council
Funding Amount
$264,358.00
Summary
Our main objective is to discover the molecular details of how cancer drugs interact with DNA and how these interactions differ from those of inactive chemically related compounds. We propose to use X-ray crystallography together with the successful methods we have developed for determining the 3-dimensional structures of the DNA complexes of a class of antitumour active drugs to study the complexes of other clinically or scientifically important DNA intercalating anticancer drugs. These agents ....Our main objective is to discover the molecular details of how cancer drugs interact with DNA and how these interactions differ from those of inactive chemically related compounds. We propose to use X-ray crystallography together with the successful methods we have developed for determining the 3-dimensional structures of the DNA complexes of a class of antitumour active drugs to study the complexes of other clinically or scientifically important DNA intercalating anticancer drugs. These agents act by poisoning the DNA binding enzyme topoisomerase. Crystallographic analysis will give us unequivocal answers at the atomic level as to the exact way in which the drug binds to DNA and how this binding differs between antitumour active and inactive compounds. We believe that a knowledge of the DNA binding mode of a class of intercalating anticancer drugs at the atomic level is valuable in guiding drug design within that class.Read moreRead less
Molecular Targeting To Telomerase And Cancer Cell Immortality By A Novel Inhibitor
Funder
National Health and Medical Research Council
Funding Amount
$430,812.00
Summary
Infinite growth of cancer cells is a hallmark of cancer. Telomerase is required for cancer cell immortality. Inhibition of telomerase may thus offer an opportunity to stop cancer cells. We have identified an inhibitor of telomerase. This project will study the mechanisms of action of the novel inhibitor, investigating how to control cancer cell immortality as a baseline for more applied anti-cancer therapeutic studies.
The Structural Basis For The Action Of Anticancer DNA-intercalating Topoisomerase Poisons
Funder
National Health and Medical Research Council
Funding Amount
$459,750.00
Summary
Cancer kills one in four people in the Western world and half of those afflicted will die from the disease. If the malignancy is detected early, surgery and radiotherapy will often effect a cure but if the disease is disseminated at presentation then treatment requires chemotherapy. Chemotherapy can be curative for some tumour types but it is generally only palliative for the overwhelming majority of solid cancers. Consequently, there is an urgent need to improve the efficacy of anticancer drugs ....Cancer kills one in four people in the Western world and half of those afflicted will die from the disease. If the malignancy is detected early, surgery and radiotherapy will often effect a cure but if the disease is disseminated at presentation then treatment requires chemotherapy. Chemotherapy can be curative for some tumour types but it is generally only palliative for the overwhelming majority of solid cancers. Consequently, there is an urgent need to improve the efficacy of anticancer drugs. Many of these drugs work by binding directly to DNA and poisoning the DNA-manipulating enzyme, topoisomerase. Our objective is to discover the molecular basis of how anticancer drugs act through their interaction with DNA and topoisomerase. We propose to use the successful X-ray crystallography methods we have developed for determining the 3-dimensional structures of the DNA complexes of a class of anti-tumour active drugs, to study the complexes of other clinically or scientifically important DNA intercalating anticancer drugs. Crystallographic analysis provides unequivocal data, at near atomic resolution, of the nature of the molecular interactions which provide specificity and selectivity in drug-DNA complexes. This information will be a valuable guide in the further development of this important class of topoisomerase poisons as anticancer drugs. We will initiate structural studies of ternary complexes between the topoisomerase enzyme, DNA and anticancer drugs. The solution of the X-ray crystal structures of these ternary complexes will allow the design of new antitumour topoisomerase poisons to be put on a completely rational basis.Read moreRead less
Investigating Tumour Maintenance Using Regulated RNA Interference
Funder
National Health and Medical Research Council
Funding Amount
$511,294.00
Summary
Inhibiting gene expression using the recently discovered process known as RNA interference (RNAi) can be used as an experimental tool to analyse specific genes, in cells and genetically engineered animal models of human disease. I propose to validate potential drug targets in cancer by using RNAi to inhibit specific genes in established mouse tumours. A further aim is to use RNAi to mimic human cancer gene mutations in mouse cancer models, to discover novel tumour suppressor genes.
Synthetic Analogues Of The Actinomycin, Quinamycin And Nogalamycin Groups Of Antitumour Antibiotics
Funder
National Health and Medical Research Council
Funding Amount
$376,433.00
Summary
The principal difficulty in the treatment of the common solid tumours that cause the majority of cancer deaths is the problem of drug resistance. For example, many patients with cancer of the lung, breast or colon respond well to drug treatment with their tumours initially regressing, only to return later in an aggressive drug-resistant form. In this event, the inevitable outcome is that the tumour grows through drug treatment and the patient eventually succumbs and dies. This is also a familiar ....The principal difficulty in the treatment of the common solid tumours that cause the majority of cancer deaths is the problem of drug resistance. For example, many patients with cancer of the lung, breast or colon respond well to drug treatment with their tumours initially regressing, only to return later in an aggressive drug-resistant form. In this event, the inevitable outcome is that the tumour grows through drug treatment and the patient eventually succumbs and dies. This is also a familiar scenario in the treatment of adults with leakaemias and non-Hodgkins lymphomas. The underlying cause of drug resistance is the genetic instability of cancer cells which results in tumours that are heterogeneous, making it almost inevitable that a cancer cell will arise that is resistant to treatment. There are many mechanisms of resistance, some of which are peculiar to particular drug types, some are permeability barriers and some involve genetic deregulation of the biochemistry of cell death. One way of subverting resistance is by the use of drugs whose mechanism of action is novel so that the tumour is challenged to devise a new defense. Here, we are attempting to develop synthetic analogues of a class of naturally- occurring antitumour antibiotic whose mechanism of action is unusual but which has not been exploited by medicinal chemists because of the difficulty of the chemistry involved. These antibiotics work by binding to DNA and inhibiting the first step in the process whereby genes are turned into proteins. We have designed compounds that are chemically accessible that our preliminary work suggests mimic the DNA-binding and biological properties of the natural antibiotics. The proposed work will enable us to evaluate whether this new class of agent has experimental antitumour activity, particularly amongst drug-resistant tumours.Read moreRead less
MMP13 is upregulated in cancer cells and in the tissue that forms around the cancer (stroma). A new MMP13-specific inhibitor reduces breast cancer growth in a mouse model, both at the primary site and also in bone. We will determine the role of MMP13 made by the cancer cells and stroma, respectively, extend the inhibitor work, and identify proteins being cleaved by MMP13. Being a late-stage manifestation, bone metastasis may represent an important clinical trial setting for MMP inhibitors.