Biomarker Identificaltion That Clicks

Collaboration between Caltech and biotechnology company Indi Molecular has led to the discovery that novel PCC (protein catalyzed capture) agent binding technology could enable creation of highly specific therapeutics for targets that have long been considered undruggable.

In a joint paper, titled, "A protein-targeting strategy used to develop a selective inhibitor of the E17K point mutation in the PH Domain of Akt1" published in Nature Chemistry, researchers describes the development of molecular binders that are targeted specifically to proteins that are disease-causing based upon a single amino acid mutation. This highly specific targeting of only the disease-associated form of the protein could allow therapeutics that avoid healthy tissues, thus reducing toxic side-effects. The paper describes the development of a PCC agent that selectively binds to and inhibits a mutated, cancer-causing form of the kinase protein Akt. The mutant protein differs from the healthy variant via only a single transforming point mutation (called the E17K mutation). The mutation increases the activity of the protein, which in turn can cause cancer. The research team believe that their strategy will be broadly applicable to a wide range of targets.

"These types of mutant proteins, or oncoproteins, are perhaps the most challenging class of cancer drug targets," said James Heath, Ph.D., co-founder and Board member, Indi Molecular; Gilloon Professor, Caltech; and senior author of the paper. "They reside within cells, and so are hidden from antibody drugs. In addition, the mutations are often not associated with binding pockets, which means that small molecule drugs, which require such pockets, can't distinguish between the mutant and healthy proteins. PCCs appear to offer a very viable alternative strategy."

"We first used an all-synthetic epitope targeting strategy to develop a small PCC agent that bound to the protein very near the site of the point mutation," said Kaycie Deyle, Ph.D., former graduate research assistant, California Institute of Technology and first author on the paper. "We then expanded the footprint of that ligand so that it blocked the binding of the protein to its target on the cell membrane. That has the effect of stopping the action of the protein. The final PCC agent inhibited the mutant protein some 1000-fold more strongly than it did the healthy variant."

PCC agents are comprised of short chain peptide molecules, each of which contributes binding affinity and selectivity characteristics towards a protein of interest. A differentiating aspect of the PCC agent technology is that the protein target itself provides a catalytic scaffold for assembling and coupling the short chain peptides – choosing across very large peptide libraries to find only those ligands that couple onto its surface in a highly selective fashion.

"The highly selective synthetic epitope targeting strategy reported in Nature Chemistry shows that Indi Molecular can now create binding molecules that have the specificity and affinity of biologics combined with a small molecule's stability and ease of manufacture," said Albert A. Luderer, Ph.D., CEO and co-founder, Indi Molecular. "The modularity of PCC agents is enabling applications in the commercial spaces of in vivo imaging, therapeutics, in vitro diagnostics and biological tools."

PCC technology was invented at Caltech and is being commercialized by Indi Molecular. The company launched as a spinout from its parent company Integrated Diagnostics (Indi) in 2013 with a $1.8 million seed round led by InterWest Partners together with Asset Management Ventures and several angel investors.

This article is a loosely edited version of a press release issued by Indi Molecular on April 13th 2015. For more information visit