Scientists in the UK say they have a new drug that may be very effective in killing tumor cells in women with well-known genetic markers of breast cancer. The new class of drugs, called PARP (Poly ADP-ribose polymerase) inhibitors, developed by Kudos Pharmaceuticals, Cambridge, is targeted to work against tumors caused by the inherited forms of breast cancer that result from mutations in the BRCA1 and BRCA2 genes.

“PARP is a family of enzymes, PARP-1 being the predominant enzyme that is involved in mediating DNA single-strand damage repair. PARP-2 is also involved to a lesser extent. The two enzymes have a degree of homology that is distinct from other enzymes and are the targets of the potent small molecule inhibitor that we have developed,” says Richard Onyett, commercial director.

Steven Jackson, PhD, chief scientific officer and founder, Kudos, began with the premise that disabling the cell’s ability to respond to DNA damage, already handicapped by the BRCA deficiency, could enhance the activity of radiotherapy and other types of cytotoxic drugs to be more efficient in killing cancer cells.

Kudos used a program of rational drug design, says Onyett. A 50,000-compound commercial library was screened for hits against the PARP target. They then followed several series of compounds and produced iterative libraries of novel molecules. Enzymatic and cellular assays were used to screen for compounds with the desired potency, selectivity, and cellular penetration.

“We were then able to go on and optimize the molecules in terms of their pharmacokinetic parameters so that we can look at the bioavailability of the molecule, and the adequate period of time in which the drug stays in the body, and improve those characteristics,” says Onyett. “This is what we have done over the last four years and have come up with a lead compound, an orally active inhibitor, which was selected because of its potential use in combination with temozolomide, an oral chemotherapeutic drug.”

In its most recent work, Kudos, collaborating with Alan Ashworth, PhD, director of the Breakthrough Toby Robins Breast Cancer Research Center, London, and other researchers, established that applying a PARP inhibitor to BRCA1 and BRCA2 deficient cells induced the killing of a large proportion of cells in vitro and in vivo.

“We believe that when you inhibit PARP in these cells deficient in BRCA1 or BRCA2, you create an environment where they are unable to repair the DNA damage that is brought on by a cancer drug,” says Onyett. However, he says, normal cells that still have all of their repair pathways intact are unaffected.

The company expects to begin clinical trials this summer. Phase I will examine pharmacokinetics and optimum dosing. Phase II will test the drug in patients with BRCA deficient tumors.

By Elizabeth Tolchin