The first meeting of the Société de Chimie Thérapeutique (SCT), called Rencontres Internationales de Chimie Thérapeutique (RICT), was organised almost 60 years ago in Lille in 1965. Looking back over those years shows how amazing the evolution of drug discovery has been.

In 1965, drugs were mainly based on small molecules (synthetic or natural) except for small proteins like insulin whose structure had been elucidated in 1951.

The first RICT were mainly devoted to the elucidation of structure-activity relationships. These RICT would today be conceived as single modality-centric meetings. One major evolution has been the extension of the topics to structure-properties relationships in the early stages of the drug discovery process. These gradually involved solubility, permeability, distribution, interaction with metabolic enzymes … that allow to improve the drug-likeness of clinical candidates.

Years later, the structure of more and more “factors” was elucidated (factors designed biologics, whose effect were well documented, but which structure remained unknown). An interesting case being tumor necrosing factor (TNF) and Cachectin (involved in septic shock) that were investigated independently by two groups who discovered when the genes were sequenced that they were chasing the same molecule. The question then arose as to whether they should be included in the topics of the RICT. The answer was that as soon as the structure can be determined and manipulated at the atomic level, these factors, now molecules, fit into the goal of drug discovery chemistry and therefore in the topics of RICT. Eventually, even the boundary between these two modalities became increasingly questionable. For instance, the design of antibody-drug conjugates has benefited of cytotoxins discovery as well as the design of improved chemical linkers.

In recent years there has been an amazing expansion of new modalities such as RNA therapeutics, gene therapy, fusion proteins, none of which could have been developed without chemical tools. Drug discovery has become “modality agnostic”. This was clearly illustrated during the recent Covid pandemic where all possible modalities were investigated at an incredible speed. By September 2022, 22 different COVID-19 medicines (6 vaccines and 16 therapeutics) had been approved or authorized by the FDA and the EMA. Although the winners were the two RNA vaccines a modality that had not at that time delivered a commercial drug, the 20 other medicines used more classical modalities such as protease inhibitors, adenovirus and protein vaccines or monoclonal antibodies.

This trend towards modality agnosticity was also true when considering the tools involved in drug discovery. High throughput screening and combinatorial chemistry have opened new path for lead discovery including in targeting protein-protein interactions that were previously considered as “undruggable”.

Biorthogonal reactions and chemical biology have added yet another dimension in the molecular aspects of drug discovery and selection. The awarding of the Nobel prize in chemistry to Morten Meldal, Barry Sharpless and Carolyn Bertozzi for the discovery of the elegant and efficient copper catalyzed or strain-promoted alkyne-azide cycloaddition is another telling example of the importance of chemistry in the discovery of new pharmaceutics, through a better understanding of biology and living organisms. Click-chemistry is becoming a corner stone reaction when probing cells and living organisms. Biologists themselves have seized on this chemistry to answer their biological questions about target function and drug action.

Becoming modality-agnostic, drug discovery now requires from researchers a broad knowledge of (bio)chemistry and structural biology together with molecular pharmacology, pharmacokinetics, and toxicology to name a few of them.

These international meetings, shared in the language of Shakespeare, as was the case for the first time for the RICT Lille in 2007, provide an ideal opportunity to update our knowledge in Drug Discovery chemistry and to better understand how this ever-evolving field contribute to the discovery of new therapies.

Prof. André Tartar University of Lille, France		Prof. Nicolas Willand University of Lille, France