PC14586: The first orally bioavailable small molecule reactivator of Y220C mutant p53 in clinical development

Dr Melissa Dumble - PMV Pharmaceuticals, Cranbury, USA

This study that I presented at AACR described the discovery of a novel small molecule that we’ve called PC14586 that was designed to reactivate a particular hotspot mutant of p53 called Y220C. The work was performed at the company that I work for, PMV Pharmaceuticals, we are a precision oncology company pioneering the discovery and development of small molecules that selectively reactivate p53 hotspot mutants.

p53 is an important protein in cancer with over 50% of all human cancers having a mutation that renders the protein inactive and non-functional. p53 is a classic tumour suppressor protein; when it’s mutant it’s really like taking the brakes off cancer cell division. So to date there has not been a therapeutic to directly treat patients who have these mutations and that’s what the talk was about. With the Y220C mutation which the molecule targets, that substitution of a tyrosine for a cysteine at the 220 amino acid of p53 results in a small crevice forming in the protein. The chemists at PMV have designed a small molecule to fit in that crevice and stabilise the mutant protein into a normal confirmation.

Then we go on to show that the small molecule engages with the target, the Y220C target, selectively, meaning it doesn’t bind or activate normal wild type p53 which spares normal tissues. It results in turning on the p53 transcriptional pathway that ultimately results in cell cycle arrest and cell death.

So, in short, we showed that the chemical reactivation of the mutant Y220C p53 really did walk and talk like a normal, or a wild type, p53. Then I finally concluded my talk telling folks how excited we are that this new investigational compound, PC14586, is in clinical trials started last September and the clinical study is a seamless phase I/II study in cancer patients with a variety of tumour types but their tumours must have that Y220C p53 mutation.

What was the methodology used in your study?

It was a very logical drug development approach to finding and characterising this molecule. The biology that we showed was very specific to p53 biology but unique because it was really the first time that anyone had shown with a chemical stabilisation of the mutant to the wild type what happens in the cells. We really ask at our company that our chemically restored mutant p53 really does look like a wild type protein. So methodology-wise the chemistry is very standard SAR, or structured activity relationship, medicinal chemistry approach where they iteratively make molecules.

The biologists at PMV test these molecules through a sequence of assays to find molecules that really did have the desired p53 biology as well as potency. We always ask that our molecules chemically reactivate that Y220C mutant p53 and have it look like normal or wild type p53. By that I mean that we can show that we can convert the confirmation from looking like mutant to looking like wild type and that that wild type can then bind to DNA, it can activate a p53 transcriptional signature and then that can result in a very p53-dependent cell cycle arrest and apoptosis.

We then optimised the molecules also to have robust pharmaceutical properties which means that we can administer them orally to either animals and of course patients once they make it to the clinic and show a robust dose responsive anti-tumour effect. We showed that in the study, that at the maximum dose this molecule results in almost complete tumour regression, sometimes a complete cure, in mouse models of cancer.

What were the key results of your study?

The takeaway from the study is that we really did describe a first in class reactivator of Y220C mutant p53 that is in clinical trials and is available to patients. The molecule is selective for Y220C mutant p53; it binds to the target and it reactivates normal p53 function. This results in robust single agent anti-tumour effect which increases with dose, so is dose responsive, and we’ve also established several biomarkers pre-clinically that we are deploying in our clinical study. For the clinicians that see this it’s important to note that the clinical study is ongoing and it’s a seamless phase I/II study that is targeting patients who specifically their tumours harbour that Y220C p53 mutation. We expect to be able to report on the safety, PK and biomarkers from this study by the end of this year, early next year.

How can these results impact the treatment and research of cancer?

To date there is no marketed therapeutic agent nor anything that we’re aware of that’s currently in development for patients that have p53 mutant tumours. This molecule really would be the first ever reactivating hot spot mutant p53. So for patients who have this Y220C p53 mutation this really is a custom-made therapeutic option for them and we really hope to be able to improve the outcome for these specific patients.

More broadly, this work is a solid proof of concept that targeting hotspot mutant p53 is a valid therapeutic approach so we’re, of course, actively working on other programmes to address other hotspot mutants. Our goal is to have custom therapies for the majority of patients whose tumours have a p53 mutation.

Then with regards to cancer research more broadly, we hope that this encourages other groups to tackle other undruggable cancer targets such as p53 which will really add to the arsenal of cancer therapeutics and provide a wider therapeutic option for patients who are in need.

Is there anything important you would like to add?

I suppose one thing we didn’t touch upon is the frequency of Y220C mutation in tumours and how we use this clinically. So the Y220C mutation is found in about 1% of human cancers and it’s found across tumour types broadly, so it’s not enriched in a particular tumour type. The tumour types where we think we might expect to see the highest number of patients include ovarian, breast, non-small cell lung, colorectal, gastric oesophageal, some of those that have a large number of patients each year. But, of course, we may see tumours from many different tissues on our clinical trial. So our clinical trial is recruiting patients with any solid tumour types, so it’s what we call a tumour agnostic trial. So long as the tumour harbours Y220C p53 mutation then we’re using a couple of different sequencing tests to confirm that the tumours do contain the Y220C mutation.

As I mentioned, and it’s probably worth mentioning again, the study is a seamless phase I/II study and we expect to be able to report on the safety, PK and biomarkers by the end of the year, early next year.