Recent Progress 2015

The past year has been an incredibly busy time for the Drug Discovery Unit (DDU). It was capped by the signing of an agreement between the group and Sixth Element Capital resulting in a £2M investment from the CRT Pioneer Fund to accelerate development of a novel lung cancer therapy targeting the RET oncogene. The DDU portfolio continues to develop and in our other advanced project, PARG, we have made significant progress, developing a biomarker strategy for patient selection and delivering compounds showing an acute pharmacodynamic effect. At the other end of the spectrum, new target identification and validation are essential to the future portfolio and we have taken steps to focus these efforts around DNA Damage Response (DDR)/Synthetic Lethality and Epigenetics. In the years ahead we will expand our partnerships and collaborations both within and beyond the Manchester Institute.

Progressing our portfolio; the way forward for the Drug Discovery Unit
At the time of this report last year, our most advanced project PARG had just moved into the lead optimisation phase. Over the past year, our lead series have been refined and optimised to deliver over a 1000x improvement in cellular potency and now also display more “drug-like” features (Figure 1). These compounds are well tolerated and show promising pharmacokinetic and pharmacodynamic profiles which will allow us to test the therapeutic potential of PARG inhibition in more relevant disease models. In addition we have developed a better understanding of the underlying genetic defects that confer cellular sensitivity to PARGi. This information will help us determine which patients are likely to respond to these agents.

Figure 1: Crystal structure of PARG with a DDU inhibitor (in Green) bound. 

Whilst PARG offers an opportunity to understand and exploit novel biology, our efforts on the RET oncogenic kinase recognises a therapeutic need for improved agents against a drug target which is already clinically validated.  The RET (Re-arranged during transfection) receptor tyrosine kinase is a known oncogene which is implicated in about 1% of non-small cell lung cancers (NSCLC). In addition to developing our existing series, during 2014 we began a new project targeting potential resistance mechanisms. Through computational and bioinformatics analysis, we have identified the likely clinical resistance mechanism and have begun the hunt for inhibitors of the resistant enzyme. Funding from Sixth Element Capital will accelerate our progress. As an indication of our success, chemical patent applications have been filed for our first lead series in both RET and PARG.

2014 has also seen the first full year of our collaboration with the GlaxoSmithKline (GSK) Epigenetics drug discovery group based in Pennsylvania, USA. In January we held our first full project team meeting looking at the output of their 1.7 million compound screen against a target of joint interest. In spite of the geographical and time differences we have developed a strong working relationship with our partners in GSK and have recently made significant progress against a very challenging epigenetics target, such that 2015 should see us make an early project phase transition.

With two projects in lead optimisation it has been difficult to grow our early portfolio and often tough priority choices have had to be made. Despite these challenges we have made good progress opposite SMARCA and mtIDH1. In terms of SMARCA, our first target derived from bioinformatics, significant progress has been made to confirm the biology around the target. For mtIDH1 a 1.4 million compound screen conducted by the DDU at AstraZeneca’s Alderley Park facility, has delivered an exciting drug-like compound series with potential for rapid progression. G6PD remains of interest biologically but is the most chemically challenging target we have worked on to date. Through our Chinese biotech partner HitGen, we have screened over 0.7 billion compounds but have yet to deliver a chemically viable series.

As mentioned in the introduction, in order to maintain a steady flow of new projects, novel target identification and validation remains of vital importance to the group. However with the resourcing pressures on the rest of the portfolio, we have decided to focus our efforts around DNA Damage Response /Synthetic Lethality, Epigenetics and Lung Cancer. To facilitate this we have empowered subgroups to reach out to potential collaborators both within and outside the Institute. We are already beginning to see the benefits of this new focus and we anticipate that our efforts will result in a strengthened early portfolio in 2015.

Technical Progress

Whist it is important to focus on the project portfolio, a great deal of technical work goes on in the background that gives meaning to the data we produce. A good example of this involves our use of the IncuCyte cell imaging system. The IncuCyte produces a kinetic read-out of cell confluency. It is ideal for the long term monitoring of cell proliferation after treatment with compounds. However when targeting the DDR we would prefer to know the exact number of cell doublings that have occurred so that we can compare effects across multiple cell lines.  Using the scripting language R, we have built an algorithm that takes the exported confluency data and allows us to generate dose-response IC50 curves for a given number of cell divisions. With multiple cell lines, this then allows us to control for the effect that the cell cycle may have on the response to a drug or DNA damaging agent (Figure 2). Furthermore, the arrival at the Institute of the first fully automated Opera Phenix will be a great boost to the operational capabilities of the DDU cell biology group.

Figure 2: Custom analysis of IncuCyte cell growth data, using a bespoke analysis package created in R by Phil Chapman. Cell confluency data is taken directly from the IncuCyte (1) and data from undosed control cell growth is analysed to determine the precise time for a specified number of cell doublings (2).  The percent confluency for cells treated with different doses of experimental agents are then determined at this specific time point (3). The data are then uploaded into our informatics system and curve fitting carried out to determine an EC50 value, comparable against different cell lines.

People

The continuing development of our staff remains of vital importance to the DDU leadership. In the summer with the help of The Research Network we held our first Drug Discovery Workshop which received extremely positive feedback. In 2014 more than 50% of our staff attended and presented our work at scientific meetings and as a group we have authored or contributed to 8 peer reviewed publications and 2 filed patent applications.

The Future
The stated aim of the DDU over the next 5 years is to deliver our first candidate drug into pre-clinical development and with the progress made on PARG and RET we are on course to achieve this. However we will only be truly successful if we can deliver our first candidate drug whilst also maintaining a sustainable ongoing portfolio. The latter is only possible through support and collaboration with our colleagues in the local and national CRUK networks.