A paper published in Nature earlier this week detailing a very early but promising novel agent for mixed lineage leukaemia (MLL) not only raises hopes for a new treatment for this aggressive cancer. The research is also encouraging news for those applying epigenetics to drug development.
The search for small molecules that can directly influence the expression of particular genes has had some success. Merck & Co’s HDAC inhibitor Zolinza, approved in 2006, works on epigenetic principles and similar agents are in development, but their mechanism of action is poorly understood and effectiveness seen so far has been limited. In the Nature paper, however, scientists showed how a novel BET inhibitor exerted its effect with impressive potency - detailing a novel mechanism of action that holds the potential for a new drug class.
MLL, a leukaemia that typically occurs in children under the age of two, is caused by the presence of proteins called MLL fusion proteins.
In its normal state the MLL protein is involved in turning on and off the genes that signal for the production of blood cells. When the gene that codes for MLL associates with a particular oncogene, the abnormal MLL fusion protein is produced; this turns on different genes which signal for the growth and proliferation of the cancerous leukaemia cells.
Researchers – a collaboration between a handful of universities, including Cambridge and Cardiff in the UK, and the companies GlaxoSmithKline and Cellzome - discovered that the MLL fusion proteins were associated with another protein, called BET. These were already known to be a regulator of gene expression which bind to chromatin – DNA structures in the cell.
They postulated that by preventing BET from binding, the signals from the MLL fusion protein could be blocked, preventing the cancer cells from proliferating. GlaxoSmithKline scientists had already identified small molecule inhibitors of BET, the paper in Nature details work with a drug called GSK1210151A.
Pre-clinical and animal studies with the drug revealed impressive potency in stopping this type of leukaemia in its tracks. Researchers now hope to take the agent into the clinic – a spokesperson for Glaxo declined to say when that might happen, adding there was still quite a bit of work to be done before tests in man could begin.
The last year or so has seen BET proteins emerge as an increasingly interesting target for drug research, as their role in gene transcription has become better understood. Constituting a family of bromodomain-containing proteins, they are sometimes called “chromatin adaptors” for their ability to recruit other proteins or entire protein complexes to the site on the chromatin where genes are regulated.
A paper published in Proceedings of the National Academy of Sciences last month showed that a gene called MYC could be blocked using a BET inhibitor. The MYC gene is thought be implicated in a number of cancers, in particular certain lymphomas and multiple myeloma. The research was backed by Constellation Pharmaceuticals; the US epigenetics specialist is working on a number of BET inhibitor candidates it hopes to take into the clinic in the next couple of years.
Meanwhile Tensha Therapeutics at the beginning of September raised $15m in a series A venture financing round to advance its bromodomain inhibitors – its lead candidate is aimed at the treatment of the very rare cancer BRD4-NUT midline carcinoma, as well as leukaemia and multiple myeloma.
Gerard Drewes, vice president of discovery research at Cellzome, believes that inhibiting BET proteins has great potential, although cautions that much work remains.
“They are promiscuous proteins, which is why they are special. They form interactions with many other proteins in the cell,” he says.
Present in many different types of cell throughout the body, BET proteins have yet to be studied broadly and their potential – and limitation - is not yet known.
“If you inhibit the BET bromodomain you can inhibit the transcription of particular defined set of genes. In inflammatory cells it’s the particular set of genes that code for inflammatory cytokines, so if you inhibit that bromodomain in inflammatory cells you can turn down inflammation,” Dr Drewes says.
The potential in epigenetics - that through the molecular inhibition of a genetic process the fate of a particular cell can be manipulated – is a long way from being realised. However, the recent Nature paper, which Dr Drewes believes is unique in detailing the mechanism of action of an epigenetic drug – and one that appears particularly potent – is an important landmark.
“This is a very exciting area for therapeutic agents with completely new mechanisms. We’re really only at the dawn of drugs with epigenetic mechanisms and this may be one of the trailblazers,” he says.