As per the regulations of the prize, the winner will be invited to deliver an oral communication at the 10th EFMC Young Medicinal Chemists' Symposium (EFMC-YMCS).

The committee would also like to congratulate the other contestants, whose presentations were of a very high level, making the final selection difficult.

• Fabio Begnini, Aarhus University, Denmark
• Elena Detta, Aicuris Anti-Infective Cures AG, Germany
• Margarida Espadinha, University of Antwerp, Belgium
• Emma Grant, University of Strathclyde/GlaxoSmithKline, United Kingdom
• Ahmed Hazem, ETH Zurich, Switzerland
• Roberta Pacifico, University of Antwerp, Belgium
• Marta Serafini, Università Del Piemonte Orientale, Italy

Congratulations to all! 

• Validating Chemical Probes

What are chemical probes and why are they important? Chemical probes are designed to selectively address a biological question; this is distinctly different from a drug, which is designed to produce a clinical outcome! Simple guidelines can be used to generate high-quality chemical probes and obtain reliable data to further our understanding of human biology and disease.

Link to the material.

• Phenotypic Drug Discovery (PDD)

Recent years have seen a renaissance of Phenotypic drug discovery (PPD) with novel screening technologies and a track record that is thought to match or surpass that of target-centric approaches. We present a view on best practices to consider when running phenotypic drug discovery campaigns to increase the chance of success of these black box approachs.

Link to the material.

• Hit Generation

Hit Generation is a crucial step of all drug discovery campaigns that will determine the speed and chance of success of identifying drug candidates.

We cover the essential approaches for hit generation and the opportunities and challenges they come with. We then provide guidance on how to validate hits to ensure medicinal chemistry is only performed on compounds and scaffolds that engage the target of interest and have the desired mode of action. Finally, we discuss the design of integrated hit generation strategies that combine several approaches to maximize the chance of identifying high quality starting points.

Link to the material.

KRAS is a GTPase protein that switches between an active (GTP-bound) and an inactive (GDP-bound) state. The study focuses on non-G12C KRAS mutants that constitute the majority of KRAS alterations in cancer and are not effectively targeted by current therapies.

The researchers began by modifying an existing G12C-selective inhibitor to remove its covalent warhead, and improve its inhibitory activity against various KRAS mutants. The resulting compound, BI-2865, demonstrated potent inhibitory effects on the proliferation of cells expressing G12C, G12D, or G12V KRAS mutants. Importantly, BI-2865 showed similar efficacy to covalent G12C inhibitors in cells expressing the G12C mutant. Kim et al. conducted structural analyses to understand the binding interactions between BI-2865 and different KRAS variants.

The crystal structures revealed that BI-2865 bound to the GDP-loaded state of WT and mutant KRAS with high affinity. The inhibitor occupied a conserved binding pocket in KRAS, similar to covalent G12C inhibitors, but without relying on a covalent bond. The drug preferentially targeted the inactive state of KRAS and inhibited nucleotide exchange, which is crucial for KRAS activation. Importantly, the pan-KRAS inhibitor selectively suppressed KRAS activation and downstream signaling in cancer cells, with limited effects on HRAS and NRAS isoforms. This selectivity was attributed to specific amino acid differences between KRAS and other RAS isoforms.

Further experiments demonstrated that the pan-KRAS inhibitor effectively inhibited the growth of various cancer cell lines harboring KRAS mutations, while having minimal impact on cells with WT KRAS or upstream-activated KRAS signaling. RNA sequencing analysis revealed that the inhibitor specifically targeted the MAPK pathway, which is commonly activated by mutant KRAS. The antiproliferative effects of the pan-KRAS inhibitor correlated with the degree of KRAS dependency in different cancer cell lines.

A derivative of the pan-KRAS inhibitor, BI-2493, was used in in vivo studies and exhibited favorable pharmacokinetic properties and potent antitumor effects in mouse models with KRAS mutant tumors, without apparent toxicity.

The study provides evidence that a pan-KRAS inhibitor can effectively target a broad range of KRAS mutants, including non-G12C variants, and inhibit downstream signaling and cancer cell growth. The findings have implications for the development of KRAS-targeted therapies in various cancer types, such as lung, colorectal, and pancreatic cancers, and suggests that pan-KRAS inhibitors may offer a wider therapeutic index compared to isoform-specific inhibitors. The results also highlight the potential of further exploring different KRAS-directed therapeutics for precision oncology treatments.

Kim, D., Herdeis, L., Rudolph, D. et al. Pan-KRAS inhibitor disables oncogenic signalling and tumour growth. Nature 619, 160–166 (2023). https://doi.org/10.1038/s41586-023-06123-3

The organising committee prepared a truly exciting event, which featured a number of distinguished scientists who delivered inspiring talks, encouraged fruitful discussions, and highlighted the importance of interdisciplinary collaboration.

The scientific programme provided the attendees with a broader perspective on the challenges faced by medicinal chemists, which will undoubtedly contribute to their own research projects.

In addition, a poster session of 105 posters allowed fruitful exchanges between the participants, who could present their research to peers in a relaxed and informal atmosphere.

The EFMC Young Scientists Network and ACSMEDI Young Medicinal Chemists Committee organised a series of networking activities to facilitate the exchanges between students and early career researchers, especially those for whom attending a conference abroad was a first experience. The programme was completed by a round table discussion on the tips to “Getting a Job in Industry”, with panellists from US and Europe sharing their experience to an eager audience.

Finally, the conference was also the occasion to meet more informally during the social programme, whether it was during the welcome reception, at the conference dinner in the beautiful restaurant Rochambeau, or during a Boston Red Sox baseball game!

We invite you all to the next edition of the meeting, scheduled to take place in Utrecht, The Netherlands on April 8-14, 2023.