Unleashing the Power of Genome Sequencing in Drug Discovery: Innovative Approaches to 'Drug the Undruggable'
At the recent annual Festival of Genomics and Biodata, Professor Paul Workman (Professor of Pharmacology and Therapeutics at the Institute of Cancer Research) delivered a keynote speech that shed light on the current state of drug discovery in the genome sequencing era.
In his delivery, Professor Workman highlighted that the rapid advancement of genomic sequencing is overtaking even drug discovery, presenting opportunities and challenges for the field. In this blog, we will explore some of the most exciting insights and the innovative approaches his team uses at the Institute of Cancer Research (ICR) to accelerate drug discovery, including examples of successfully 'drugging the undruggable' cancer genomes.
Genome Sequencing Outpacing Drug Discovery
According to Professor Workman, the speed, completeness, and relatively low cost of genome sequencing have resulted in an abundance of new drug targets and biomarkers. However, the drug discovery process, from idea to approved drug, still takes up to 20 years, lagging behind the rapid pace of genome sequencing (source: Professor Paul Workman's keynote speech at the Festival of Genomics). This discrepancy presents a challenge for researchers to catch up and fully harness the potential of genome sequencing in drug discovery.
Innovative Approaches at the ICR
To bridge the gap, Professor Workman and his team at the ICR are using innovative and creative methods to accelerate drug discovery, including finding ways to 'drug the undruggable'. One example highlighted at the festival is the discovery of the AKT inhibitor capivasertib. This discovery boasts promising results in extending progression-free survival in advanced ER+ breast cancer patients in phase III clinical trials (source: Professor Paul Workman's keynote speech at the Festival of Genomics). Underpinning this success was “key basic structural biology research at the ICR, which enabled rapid fragment-based drug design in partnership with Astex Therapeutics”.
Another groundbreaking example discussed by Professor Workman is a drug that has recently entered phase I trials and has shown promise in animal models for patients with ovarian cancers resistant to chemotherapy. This drug indirectly targets HSF1, a transcription factor or "master switch" that controls gene activity within cells, which has long been considered undruggable due to its lack of suitable cavities or grooves for drug binding. To overcome this challenge, Professor Workman's team used a unique approach called 'phenotypic cell-based screening'. Instead of starting with the molecular target and designing a small-molecule drug, they screened for “chemicals that switched off the HSF1-mediated gene activation pathway and worked backwards to identify the precise molecular mechanism of action”.
Results and Future Directions
The team at the ICR successfully identified a small-molecule drug candidate (NXP800), which blocks the HSF1-mediated gene activation pathway. It also shows vigorous anticancer activity in animal models of drug-resistant ovarian and endometrioid cancer (source: Professor Paul Workman's keynote speech at the Festival of Genomics). This example highlights the power of innovative approaches in drug discovery, where thinking outside the box and leveraging the latest technologies can lead to groundbreaking results and the potential to 'drug the undruggable'.
Although genome sequencing is currently surpassing drug discovery in speed and completeness, innovative approaches, as Professor Paul Workman and his team demonstrated, are instrumental in levelling the playing field.
As we continue to advance our understanding of the human genome and its role in disease, the potential for genome sequencing to drive drug discovery and therapeutic development is immense.
Keep your eyes peeled for the next instalment of our series, where we unpack another intriguing update from the Festival of Genomics & Biodata 2023; ‘Harnessing the Potential of Genomics: Empowering Cancer Care through Inherited Mutations and Equitable Access to Genomic Testing’. To learn more about Genefirst’s sequencing technologies for use in drug discovery, get in touch with one of our experts.