Biotherapeutic Development - Magic Roundabout

Background

Magic Roundabout (Robo4/ECSM4) is a distant homologue of the Roundabout family that is traditionally implicated in neuronal guidance. Magic Roundabout was identified by a team led by Prof. Roy Bicknell at the Molecular Angiogenesis Laboratory, Weatherall Institute for Molecular Medicine, Oxford. It is a transmembrane receptor that is specifically expressed in endotheial cells of angiogenic blood vessels.

Together, the tumour-specificity of Magic Roundabout expression and its potential role in angiogenesis highlights the receptor as an exciting candidate for development of tumour targeting agents.      

The Collaboration

CRT's scientists collaborated with Prof Bicknell's laboratory to generate and characterise anti-Magic Roundabout monoclonal antibodies and to synthesise soluble receptors for expression and functional analysis.

Through the reagents provided by CRT, Prof. Bicknell’s laboratory was able to demonstrate that soluble Magic Roundabout receptor inhibits endothelial cell migration and invasion. This provided evidence that Magic Roundabout plays an important role in angiogenesis and thereby validated Magic Roundabout as an exciting target for therapeutic intervention and diagnostic applications.

The Magic Roundabout antibodies, soluble receptor and associated patent portfolios were subsequently out-licensed to a major biotechnology company.

Project Status

Magic Roundabout is currently under preclinical development by the Magic Roundabout licensee.

Drug Discovery - PKD

Background

Protein Kinase D (PKD, PKCµ) plays a central role in tumour cell survival, proliferation and invasion in a number of cancer types (including breast, colorectal and pancreatic). However, it remains a novel target for anti-cancer drug discovery and inhibitors of PKD are likely to be first-in-class agents with significant clinical and commercial potential.

There is also increasing evidence that PKD is involved in hyperproliferative skin disorders (psoriasis etc.) and in cardiac hypertrophy, indicating that inhibitors of PKD will have application in multiple therapeutic areas.

The Collaboration

The PKD drug discovery programme is led by CRT in collaboration with Prof Doreen Cantrell of the University of Dundee and Prof Peter Parker of the Cancer Research UK London Research Institute (LRI).

Several series of compounds have been identified and developed from a screen of CRT’s compound library. The lead series has been the subject of an intense hit-to-lead and lead optimisation programme that has improved the potency of the original hits by over 500 fold.

The most potent compounds inhibit PKD with IC50 of <1 nM and these compounds show good selectivity against a panel of diverse kinases.

Investigation of in vitro ADME properties of the compounds has indicated that they are soluble, cell permeable and have promising CYP450 inhibition and microsomal stability profiles.

Cell based studies have shown that the lead compounds inhibit PKD auto-phosphorylation and activation and also inhibit proliferation of pancreatic cancer cells in response to growth factors with low µm potency. In addition, the lead compounds are potent inducers of apoptosis.

Project Status

The lead compounds are currently undergoing pharmacokinetic studies in advance of proof of efficacy studies.