Chemistry plus biology equals less cancer

Bringing together the fields of synthetic chemistry and biology forms the perfect union with which to study biological molecules involved in pathological processes. It is also uniquely positioned to design drugs according to biological targets.

Chemical biologists initiated the EU-funded project 'Using chemical-biology to synthesis and study nuclear receptor proteins' (CHEMBIONMR) to untangle some of the molecules and parts of molecules important in breast cancer. The focus was on oestrogen receptors (ORs). About 75 % of all breast cancers are ER-positive meaning that oestrogen causes them to grow.

Post-translational modifications (PTMs) of molecules occur after ribosomes translate the code of messenger RNA into specific amino acid chains. They play critical roles in the subsequent functions of many molecules and are important targets for drug therapies. They are also important to OR function.

Until now, it has been quite challenging to synthesise well-defined OR constructs containing PTMs. CHEMBIONMR accomplished this task, successfully introducing PTMs at one end of the OR ligand binding domain, the region of the OR that binds oestrogen. In order to probe the effects of the PTM on OR activity, researchers also introduced a fluorescent probe in a site-specific way.

Investigators employed a number of biophysical techniques (fluorescence polarisation, circular dichroism and nuclear magnetic resonance) and molecular dynamics simulations. The results revealed a PTM (phosphorylation)-dependent but ligand-independent pathway to OR activation.

This is particularly important in understanding why some forms of breast cancer are OR-negative and resistant to the drug tamoxifen. Tamoxifen is an OR antagonist, a molecule resembling oestrogen that competes with it at the OR ligand binding site. Administration of tamoxifen may not reduce cancer progression in some cases because OR activation is dependent on phosphorylation of the receptor, not ligand binding.

CHEMBIONMR has not only advanced understanding of breast cancer and mechanisms of activation of OR, providing a therapeutic target. It has also delivered important tools for studying the PTMs so critical to cellular signalling and molecular function. Outcomes are expected to speed the understanding of disease processes and the subsequent development of novel therapies with benefits for millions worldwide.