EUREKA project E! 1948 SASTEREC and its follow-up E! 2705 SAMARDES carried out essential research with the human androgen receptor to understand the mechanism of the mode of action of androgens. The human androgen receptor (hAR) binds the male sex steroids and regulates genes for male differentiation and development.
The lengthy and meticulous research began in 1998 with E! 1948 SASTEREC. Structural evidence was found for fine-tuning ligand specificity in the binding domain of the human androgen receptor. This project identified and categorised the critical hormone binding sites through crystallisation and X ray determination of the 3D structure, and studied how they docked and acted. The researchers then tested the sites with agonists and antagonists to assess their possible use as hormone-based drugs to control tumours.
In E! 2705 SAMARDES, the research was extended to include investigations into mutated forms of the human androgen receptor (hAR). This work is important as 14 known mutations of hAR are known to be associated with either prostate cancer or partial or complete androgen receptor insensitivity syndrome. A double mutant of this receptor derived from an independent cancer line that had been shown to have glucocorticoid activity was structurally characterized.
"The two projects form a continuous sequence of research aiming to understand the mode of action of androgens. With the structural data in hand, the development of drugs that bind to the ligand binding domain of these receptors could become easier and lead to more effective treatments with fewer side effects," explains Professor Maria Armenia Carrondo of the Portuguese Instituto de Biologia Experimental e Tecnologica (IBET).
"EUREKA has provided us with a fantastic opportunity. It has enabled us to build up an excellent partnership with a leading company and to be involved from a very early stage of the research." Manuel Carrondo, CEO Instituto de Biologia Experimental e Tecnologica (IBET) Portugal
These two EUREKA projects have forged an eight-year partnership between the leading pharmaceutical company in steroid hormones (Schering, Germany) and IBET. "Schering has had an extremely fruitful collaboration with Professor Carrondo and her group for many years. It is this exchange of expertise and ideas between two organisations which leads to such positive results," says Professor Dr Peter Donner, Head of Protein Chemistry at Schering.
In terms of research and knowledge gained, the partners describe the projects as being 110% successful, having led to new patents and published papers. These will lead, in turn, to co operation with other patent holders to produce anti-cancer drugs for clinical trial and the market.
According to Manuel Carrondo, CEO of IBET, the importance of the projects goes well beyond the research itself. "It is critical for us in a small country to work with the top European companies and the success of these projects will help us to further convince our government of the importance of international cooperation."
"EUREKA has provided us with a fantastic opportunity. It has enabled us to build up an excellent partnership with a leading company and to be involved from a very early stage of the research."