Domainex recently participated in the 33rd Medicinal Chemistry in Eastern England conference. This was the first time in three years that the conference had been held as an in-person event, and it certainly was great to be back seeing familiar faces and re-connecting with the local research community.
The majority of the speakers at the conference gave details of small-molecule drug discovery campaigns, with the most common end-point being a pre-clinical candidate. Across all presentations, it was intriguing to see how the molecular structure evolved over each project to yield the final chosen compound, highlighting the significance of key structural features to obtain the desired properties.
Nick Martin (Associate Principal Scientist, Medicinal Chemistry) gave a presentation on behalf of Domainex, on the Development of MAP4K4 Inhibitors for the Suppression of Cardiac Muscle Cell Death. He described how Domainex applied its virtual screening platform, LeadBuilder, to identify initial hit compounds, then focussed on key interactions with MAP4K4 to identify compounds with increased potency and selectivity. Further lead optimisation work targeted improvements to the pharmacokinetic properties. A pro-drug strategy was ultimately pursued in order to achieve the aqueous solubility required for the planned intravenous route of administration. Nick went on to describe proof-of-concept studies in mouse and pig. Further details of this project can be found in the case studies section of our website (click here).
Steve Watson of Sosei Heptares and Samantha Hughes of AstraZeneca gave engaging talks on projects showing promising results. Steve gave a history of a GPR52 agonist (HTL0041178) up to and including a strong pre-clinical data package, demonstrating its potential as a novel non-dopaminergic, anti-psychotic and pro-cognitive method to treat schizoaffective disorder. Samantha described a selective estrogen receptor degrader (SERD) (AZD9833) which has already entered into clinical trials. If successful, this will provide an orally administered alternative to the existing drug Fulvestrant, which has to be injected directly into muscle tissue.
The use of proteolysis targeting chimeras (PROTACs) as a method to achieve targeted protein degradation has grown rapidly in recent years and is an area that Domainex has a strong interest in and is actively working in. Martin Ambler described a PROTAC project carried out at LifeArc in which MNK (kinase) was the protein targeted for degradation. He gave details on efforts to improve the ADME properties through variation of the linker group, with the top choice being an interesting spirocyclic di-piperidine structure. In a related area of research, Shane Rountree of Almac Discovery gave an interesting talk on the inhibition of USP19, a deubiquitinating enzyme (DUB). The aim of the approach is to prevent deubiquitination of a ubiquitinated protein to allow it to be degraded by the 26S proteasome, which results in a similar outcome to PROTACs that effect ubiquitination of the protein for the same purpose.
In contrast with the traditional drug discovery presentations, two talks took a more technological angle, providing insight into how the industry is embracing new and more efficient ways to discover drugs. The first of these talks was given by Jeremy Besnard, in which he enthusiastically communicated Exscientia’s application of artificial intelligence (AI) across the drug discovery process; three of their AI-designed molecules have progressed into clinical trials. The second talk was given by Neal Fazakerley of GSK. He described GSK’s adoption of up-to-1536-well plates for carrying out chemistry that can go directly into biological screening, and then elaborated on the computational strategies required to design and process such arrays.
Domainex was represented at the event by Ray Boffey (Executive Director of Medicines Research), Rachel Pearce (Associate Director, Business Development), Nick Martin (Associate Principal Scientist) and Nick Chapman (Senior Scientist II, Chemistry).
If you would like to get in touch with us regarding any part of our integrated drug discovery services, then please visit the contact us page of our website (click here).