CRT Discovery Laboratories: A proven partner for progressing academic research to clinical trials

CRT Discovery Laboratories (CRT-DL) has successfully worked with CRUK scientists and industry partners to discover a first-in-class, orally-active, and highly selective Protein Kinase C (PKC) inhibitor which is now progressing towards Phase I trials.

The drug targets PKC iota (PKCι), a key player in cell growth, establishment and maintenance of cellular polarity, and migration, and which is found to be amplified in many carcinomas. The potential of PKCι as a target was identified by Professors Peter Parker and Neil McDonald working on PKCι signalling pathways and its structural biology at the Francis Crick Institute. They turned to CRT-DL and its collaboration partner, Teva Pharmaceutical Industries, who designed a drug discovery programme leading to a clinical candidate that could successfully modulate PKCι. The drug discovery collaboration was highly iterative, explains Parker, involving the Crick teams throughout. “Our role as academics is to deepen knowledge and insight. Hence we can invest time and effort into extracting this depth of understanding and then contribute this to create a well informed development and trial activity.”

“I believe this is the first research collaboration to demonstrate that selective small molecule inhibitors against a key regulator of cellular polarity can be efficacious in models of human cancer”, says Dr Jon Roffey from the CRT-DL. Dr Christian Dillon from CRT-DL added, “A significant breakthrough has been identifying a set of small molecules that possess strong anti-cancer activity, yet are well tolerated in animal models and maintain suitable properties for further development.”

Several other important outputs have come from the project, including early work on solving the co-crystal structure of PKCι and identifying its binding motifs. Additionally, using an inhibitor-resistant mutant of PKCι, the team has invented a novel methodology for kinase substrate identification, dubbed Kinase Identification of Proximal Substrates (KIPS). The method enables the identification of kinase activity biomarkers, removing a significant barrier to drug discovery and development.

Finally, some of the well characterised compounds discovered during the collaboration have been fed back into academic research as declared tool compounds. The PKCι inhibitors provide a means of acutely blocking protein function and exploiting these in model organisms is having a profound impact on understanding the cellular functions of PKCι. These tool compounds are now accessible to the wider academic community.

Ignyta have now licensed the programme, and Parker is actively involved in facilitating the progression of the inhibitor to Phase I trials. Parker hopes that the compound could be effective in inhibition of tumour growth and metastatic spread in a broad range of carcinomas. “By working in collaboration with CRT and our industry partners, we are seeing a drug candidate progress to its first patients in the coming months, something that otherwise may not have occurred for years.”

This story was originally published in Pioneering Research: Cancer Research UK’s annual research publication for 2014/15. Find more at cruk.org/pioneeringresearch