Small molecules as anticancer drugs
Breast cancer affects more women in the developed world than any other type of cancer. In most cases, the breast cancer cells contain a protein receptor that attaches to the hormone oestrogen, which in turn fuels the cells' growth. These oestrogen receptor-positive (ER+) cells can be treated with drugs that block the receptor from binding oestrogen. However, many patients either do not respond well to the drugs, known as oestrogen receptor (ER) inhibitors, or develop resistance to them. The EU-funded NHELMIMACANL (Novel alpha-helix mimetics as anti-cancer leads) initiative sought to develop alternative drugs that would either replace or complement ER inhibitors. They focused on another receptor, liver receptor homologue 1 (LRH-1), which acts together with ER to regulate breast cancer cell growth. For LRH-1 to work, it needs to bind to other proteins called co-activator proteins. One way to stop it working is therefore to design a drug that blocks the part of the co-activator protein molecule that attaches to LRH-1. Researchers studied the structure of the area where both LRH-1 and co-activator proteins bind, and then designed small molecules containing a similarly shaped structure. The idea was that these small molecules, known as mimetics, would bind to LRH-1 in place of the co-activator proteins, inhibiting its action. Since similar interactions also occur in receptor proteins implicated in prostate cancer, small molecules mimicking these binding sites were also targeted as the basis for new anti-prostate cancer drugs. Although researchers completed the key steps towards making the mimetics, the final products could not be tested due to unexpected chemical reactivity. A new synthetic route designed to avoid undesired reactions should soon provide the pharmaceutical industry with promising anticancer lead molecules as co-therapies to current drugs.
Keywords
Anticancer drugs, breast cancer, protein receptor, oestrogen, NHELMIMACANL, mimetics
