BioWorld International Correspondent
LONDON - Astex Technology Group plc claimed a validation of its fragment-based drug discovery platform, with approval for a clinical trial of AT 7519, a cyclin-dependent kinase (CDK) inhibitor, just 14 months after it first synthesized the compound.
That's less than half the industry average, said Harren Jhoti, chief scientific officer. "When I worked at GlaxoSmithKline, the attrition rate [in discovery] was 80 percent. In other words, 80 percent of chemistry was a waste of time, energy and effort, and slowed the whole process down.
"With our fragment-based approach, the numbers are reversed. There are only 10 to 20 percent [of compounds] we can't do anything with," he told BioWorld International.
Astex's approach is rooted in experimental data, in that it uses high-throughput X-ray crystallography to identify drug fragments bound to protein targets. That distinguishes it from structure-based drug discovery approaches that screen chemical libraries against known protein crystal structures in silico.
Astex then uses its medicinal chemistry expertise to build the fragments into leads. Only atoms that contribute to binding are added to the fragments, resulting in low-molecular-weight compounds. Because there are no redundant atoms, there is less likelihood the molecules will have undesirable properties.
"The outsourcing company manufacturing our lead product said it was the simplest compound they have ever had to make," Jhoti said.
The power of Astex's Pyramid platform has been demonstrated also in a number of research programs with pharmaceutical partners in which it has been used to design drugs against targets that were considered previously to be intractable.
AT 7519 is an intravenously administered cell-cycle inhibitor designed to cause tumor shrinkage in a range of xenograft models. "The differentiator between this compound and other CDK inhibitors currently in clinical development is potency," Jhoti said. "AT 7519 is at least twice as potent." The compound now will enter a multicenter UK Phase I trial in patients with refractory solid tumors.
Following closely behind is AT 9283, an aurora kinase inhibitor, which Astex plans to file for clinical trial approval before the end of 2005, and AT 9311, an orally available CDK inhibitor, with an investigational new drug application filing planned for early 2006.
Astex raised £23 million (US$42 million) when it acquired MetaGen Pharmaceuticals GmbH in November 2003, providing funding to advance the three compounds into clinical trials. The Cambridge-based company said it is in discussions with partners on preclinical- and clinical-stage out-licensing.