How has drug discovery at DNDi evolved over the past decade?

 

Portrait of Robert Don

Dr Robert Don, Discovery and Pre-Clinical Director at DNDi (2005-2017), reflects on challenges and achievements in drug discovery at DNDi over the last 12 years.

I joined DNDi in March 2005 to work in discovery – a three-stage process consisting of screening, lead selection, and lead optimization – essential to bringing forward new drugs.

At that point, there were no pre-existing consortia working on ‘our’ diseases as there were for other product development partnerships (PDPs). We were just working through bilateral agreements with pharmaceutical companies and screening centres. Over the last twelve years, we have consolidated our efforts, built up teams, and followed the usual pharmaceutical process for discovering new drugs.

We set up three consortia that undertake hit-to-lead and lead optimization activities for visceral leishmaniasis (VL) and Chagas disease in the US, Australia and, since 2013, Brazil. The latter is particularly significant as it is DNDi’s first neglected disease earlystage research programme launched in an endemic region.

DNDi is now starting to explore ‘open innovation’, an approach to drug discovery in which different actors actively collaborate without the restraints of intellectual property. We are venturing into this by three routes:

Firstly, open source drug discovery, in which all data and ideas are freely and immediately shared, and anyone may participate at any level. Typically, after a single hit has been identified, a large number of analogues are synthesized and tested. In the search for a preclinical candidate for Chagas disease, we produced and characterized 1,000 analogues of the antifungal agent fenarimol. This data set has been shared with the Open Source Drug Discovery project at the University of Sydney to facilitate the search for drugs for mycetoma.

“DNDi has demonstrated that it can build a credible drug discovery pipeline. As I retire, I am leaving an organization that is facing future challenges in a spirit of openness and innovation.”

 

The second approach is the NTD Drug Discovery Booster, in which five pharmaceutical companies conduct a multilateral, simultaneous search of the millions of compounds in their compound libraries based on an active seed compound supplied by DNDi.

The most interesting compounds are tested and fed back into the process, refining the search in an iterative manner. This beautiful example of a productive collaboration between pharmaceutical companies and PDPs has surpassed my expectations: four hit series have been approved already thanks to a vastly accelerated process. The Booster runs at very little cost to either side – we estimate that each iteration saves about USD 90,000 compared to running the process in a conventional manner, and we have done 22 iterations so far. Although precompetitive research is not a new idea, the Booster takes it in a new direction.

Thirdly, we have been looking at ways to incentivize crowd-sourcing with the Open Synthesis Network. We have approached universities with real problems from our lead optimization programme and suggested analogues of hits that we would like to test. Final year undergraduates and graduate students, who would otherwise synthesize well-known compounds that are then discarded, are given the challenge of synthesizing these analogues. These are then tested and the data returned to the students, who may then propose further analogues for testing, building up a rich source of information that may ultimately lead to the development of a lifesaving drug. We started the project with five universities – Imperial College London (UK), Pace University, New York, and Northeastern University, Boston (US), the Indian Institute of Chemical Technology, Hyderabad, and the Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management at Narsee Monjee Institute of Management Studies, Mumbai (India) – who are very enthusiastic about this approach. This project is open to expansion to other universities.

The biggest challenge for open innovation lies ahead, in the next step of the drug discovery process, getting beyond an optimized lead. This ‘valley of death’, in which the vast majority of compounds fail, is expensive and requires good laboratory practice capacity, both are major barriers to academic involvement.

With the development of fexinidazole and acoziborole for sleeping sickness and a promising pipeline of new compounds from oxaborole and nitroimidazole series for VL, DNDi has demonstrated that it can build a credible drug discovery pipeline. As I retire, I am leaving an organization that is facing future challenges in a spirit of openness and innovation.

 

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Read more about DNDi‘s Open Innovation Portal