Box 1. The development and validation of LDC1267.

In 2008, Axel Ullrich and co-workers published evidence that the TAM receptor family protein AXL receptor tyrosine kinase (AXL; UFO) promotes metastatic behavior of cancer cells in culture. The group also showed that inhibition of AXL abrogated the behavior.6

Ullrich is director and a professor of molecular biology at the Max Planck Institute of Biochemistry.

Bert Klebl, managing director and CSO of Lead Discovery Center GmbH (LDC), said that the findings were the starting point for a collaboration to optimize tyrosine kinase inhibitors against the TAM receptors.

Profiling and cellular characterization of the inhibitors were done in an iterative process with LDC and Max Planck scientists. "LDC optimized not only the selectivity and potency but also the physiochemical and pharmaceutical properties to yield bioavailable TAM receptor kinase inhibitor leads, which have shown proof of concept in a couple of animal models for cancer," said Klebl.

LDC1267 was rationally designed using a pharmacophore-based approach and was selected from hundreds of compounds based on activity in cell-based AXL autophosphorylation assays.

LDC1267 binds the target kinases with nanomolar affinity in vitro. It is selective for the TAM receptor kinases from a panel of 456 kinases tested both through cell-free KINOMEscan assays and, in cells, through quantitative proteomic assays.           -AD