A Star in the Making

The listing of the collaboration with Professor Sir David Lane of A*Star, alongside Genentech, in the latest Operational Update tends to elevate the importance of the academic research work with Lane. So what do we know about the collaboration - a little or a lot?

We do know, courtesy of the Update, that Phylogica's FPPs are able to enhance the delivery of their peptides more effectively than other CPP approaches. The rest is mostly conjecture based upon scientific papers by authors from the p53 lab and work by Phylogica on related targets. The common thread appears to be the MDM-p53 pathway.

Borrowing from a previous post in the thread Guardian of the Genome, it was noted that Lane may be interested in the FPP platform for intracellular delivery of cargo payloads targeting the MDM-p53 pathway rather than the dual targeting of p53 and Myc;

"We need to go back the March 2015 presentation and slide 27 titled MDM/p53 as a drug target in Cancer. Phylogica discusses a DPMI-a peptide that binds MDM2 with high affinity but can't penetrate cells. A FPP-DPMI-a enhances the delivery of the peptide into breast cancer cells. SoT covered it in his post of 2 March 2015, "so it’s possible [FPP] 1746 could be linked to not only omomyc, but to other protein drug molecules [such as DPMI-a] that to-date have been unable to efficiently access inner cellular targets".

In the article published in July 2015, Assessing the Efficacy of Mdm2/Mdm4-Inhibiting Stapled Peptides Using Cellular Thermal Shift Assays which includes several authors from the p53 lab including Lane, we find a reference to the intrinsic problem plaguing peptide inhibitors against MDM2/MDM4-p53 interactions. Whereas the new class of drugs have the potential to be optimised for high binding affinity and specificity, the mechanism for cellular uptake, cellular availability and intracellular binding is still elusive.

In the article published in March 2014, Drugging the p53 pathway: understanding the route to clinical efficacy by authors including Lane, the subject of toxicity is discussed in initial clinical trials where inhibitors of MDM2 have shown efficacy but hint at on target toxicities.

ds made the point in his recent post covering the conference call, that Hayes seemed very relaxed about toxicity given that toxicity would normally be the part that would keep him awake at night.

Does the collaboration with Lane involve the intracellular delivery of peptide cargoes against MDM2-p53 interactions? If so, can we sleep easily about toxicity and the effectiveness of FPPs in relation to cellular uptake, cellular availability and intracellular binding. Myc is a blockbuster target but so is p53.