Highlights from the Lowlands: Early Career Researchers Shine at Medicinal Chemistry Frontiers 2024 The annual EFMC-ACS MEDI Medicinal Chemistry Frontiers was held in Utrecht in Spring 2024. Summarized here are some of the major themes from the event, including the enriching research contributions ...

Just published in #ChemMedChem (@chemistryeurope.bsky.social): Highlights from the Lowlands: Early Career Researchers Shine at Medicinal Chemistry Frontiers 2024 #MedChemFrontiers24

chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/...

Had an amazing time at #MedChemFrontiers24 by the EFMC and ACSMEDI. Thank you to all speakers, poster presenters and participants for making this such an exciting event. The quality of all contributions was truly outstanding. Also amazing to see the very active EFMC Young Scientists Network.

Inspiring talk by George Vandeveer from Biogen at #MedChemFrontiers24. He talked about their work on the covalent, brain-penetrant BTK inhibitor BIIB-129 based on (substituted) acrylamides for applications in multiple sclerosis.

Coumarin‐Rasagiline Hybrids as Potent and Selective hMAO‐B Inhibitors, Antioxidants, and Neuroprotective Agents Parkinson's disease is highly prevalent, and there is no cure for it. New therapeutic solutions need to be developed urgently. Coumarin-rasagiline hybrids were synthesized and studied as hMAO inhibit....

Interesting talk by Maria Joao Matos at #MedChemFrontiers24. She talked about her group's amazing research on hybrid compounds for neurodegenerative diseases. chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1...

Interesting talk by Rachel Lagiakos of Schrödinger at #MedChemFrontiers24. She talked about the many ways, in which computational methods can support drug discovery on the example of KAI-11101, a brain penetrant DLK inhibitor for neurodegenerative diseases.

A Mild Synthesis of Aryl Triflates Enabling the Late‐Stage Modification of Drug Analogs and Complex Peptides We report a highly convenient strategy to convert phenols into the corresponding aryl triflates using a newly discovered reagent in presence of a fluoride source. The reactions are generally complete....

Interesting talk by Stefan Schiesser at #MedChemFrontiers24. He talked about the importance of new synthetic methods for drug discovery. Interesting insights into late-stage functionalization of phenols and into the synthesis of N-CF3 amines. chemistry-europe.onlinelibrary.wiley.com/doi/full/10....

Store-Operated Calcium Entry as a Therapeutic Target in Acute Pancreatitis: Discovery and Development of Drug-Like SOCE Inhibitors Store-operated calcium entry (SOCE) is important in the maintenance of calcium homeostasis and alterations in this mechanism are responsible for several pathological conditions, including acute pancre...

Interesting talk by Tracey Pirali at #MedChemFrontiers24- She talked about her group's research on using click chemistry in drug discovery as well as the advantages and disadvantages that this brings with it. pubs.acs.org/doi/10.1021/...

Introduction to Microelectrode Arrays, the Site-Selective Functionalization of Electrode Surfaces, and the Real-Time Detection of Binding Events Microelectrode arrays have great potential as analytical tools because currents can be independently measured at each electrode in the array. In principle, these currents can be monitored in order to ...

Interesting talk to open the last day of #MedChemFrontiers24 by Kevin Moeller. He talked about his group's exciting work on selectively making microelectrode arrays and using them for diagnostic of bacterial infections by detecting multiple metabolites. pubs.acs.org/doi/abs/10.1...

Discovery of WD Repeat-Containing Protein 5 (WDR5)–MYC Inhibitors Using Fragment-Based Methods and Structure-Based Design The frequent deregulation of MYC and its elevated expression via multiple mechanisms drives cells to a tumorigenic state. Indeed, MYC is overexpressed in up to ∼50% of human cancers and is considered ...

Insightful talk by Stephen Fesik at #MedChemFrontiers24. He talked about his group's pioneering work on fragment-based drug discovery for undruggable targets such as Bcl-xL, KRAS and MYC. pubs.acs.org/doi/10.1021/...

Protease Activated Probes for Real-Time Ratiometric Imaging of Solid Tumors Surgery is the preferred treatment option for most solid tumors. However, inaccurate detection of cancer borders leads to either incomplete removal of malignant cells or excess excision of healthy tissue. While fluorescent contrast agents and imaging systems improve tumor visualization, they can suffer from low signal-to-background and are prone to technical artifacts. Ratiometric imaging has the potential to eliminate many of these issues such as uneven probe distribution, tissue autofluorescence, and changes in positioning of the light source. Here, we describe a strategy to convert quenched fluorescent probes into ratiometric contrast agents. Conversion of the cathepsin-activated probe, 6QC-Cy5, into a two-fluorophore probe, 6QC-RATIO, significantly improved signal-to-background in vitro and in a mouse subcutaneous breast tumor model. Tumor detection sensitivity was further enhanced using a dual-substrate AND-gate ratiometric probe, Death-Cat-RATIO, that fluoresces only after orthogonal processing by multiple tumor-specific proteases. We also designed and built a modular camera system that was coupled to the FDA-approved da Vinci Xi robot, to enable real-time imaging of ratiometric signals at video frame rates compatible with surgical workflows. Our results demonstrate that ratiometric camera systems and imaging probes have the potential to be clinically implemented to improve surgical resection of many types of cancer.

Great talk by Franco Faucher from Matt Bogyo at #MedChemFrontiers24. He talked about his exciting work on fluorescent tools that selectively label tumors and can be used to guide surgeons to completely remove tumors during surgery. pubs.acs.org/doi/full/10....

Design, Synthesis, and Evaluation of Inhibitors of Hedgehog Acyltransferase Hedgehog signaling is involved in embryonic development and cancer growth. Functional activity of secreted Hedgehog signaling proteins is dependent on N-terminal palmitoylation, making the palmitoyl t...

Great talk by Efthymios Gavriil from the Ed Tate group at #MedChemFrontiers24. He talked about his exciting work on targeting Hedgehog signaling through inhibition of its acyltransferase HHAT. A very exciting and thorough medicinal chemistry project. pubs.acs.org/doi/10.1021/...

Identification of Potent and Selective Glucosylceramide Synthase Inhibitors from a Library of N-Alkylated Iminosugars Glucosylceramide synthase (GCS) is an important target for clinical drug development for the treatment of lysosomal storage disorders and a promising target for combating type 2 diabetes. Iminosugars ...

Great talk by Kyle Landskroner from Azafaros at #MedChemFrontiers24. He talked about nizubaglustat for treating lysosomal storage disorders - a clinical candidate that started in the labs of Hans Aerts, Richard van den Berg and Hermen Overkleeft @led3hub.bsky.social. pubs.acs.org/doi/10.1021/...

Covalent drugs targeting histidine – an unexploited opportunity? Covalent drugs and chemical probes often possess pharmacological advantages over reversible binding ligands, such as enhanced potency and pharmacodynamic duration. The highly nucleophilic cysteine thi...

Amazing talk by Lyn Jones from the Dana Farber Cancer Institute at #MedChemFrontiers24. Exciting insights into the systematic investigation of molecular glue degraders and the use of covalency beyond cysteine in molecular glues. pubs.rsc.org/en/content/a...

Development of Orally Bioavailable Peptides Targeting an Intracellular Protein: From a Hit to a Clinical KRAS Inhibitor Cyclic peptides as a therapeutic modality are attracting a lot of attention due to their potential for oral absorption and accessibility to intracellular tough targets. Here, starting with a drug-like...

Great talk by Ryuji Hayashi from Chugai Pharmaceuticals at #MedChemFrontiers24. He talked about the synthesis of mid-sized cyclic peptides and their use for the engagement of intracellular targets. Exciting insights into rules how to make them "drug-like". pubs.acs.org/doi/abs/10.1...

Design and Characterization of an Intracellular Covalent Ligand for CC Chemokine Receptor 2 Covalently acting inhibitors constitute a large and growing fraction of approved small-molecule therapeutics as well as useful tools for a variety of in vitro and in vivo applications. Here, we aimed ...

Great talk by Natalia Ortiz Zacarias of the LACDR of Leiden University @led3hub.bsky.social at #MedChemFrontiers24. She talked about her work with an NWO Veni grant on developing modulators for CC Chemokine Receptor 2 (CCR2). pubs.acs.org/doi/10.1021/...

Great start to the day at #MedChemFrontiers24 with an EFMC-YSN panel discussion hosted by Sean McKenna. Important insights by Hayley Binch, Luc Brunsveld, Silvia Illa Tuset, Mark Murcko and Floris van Delft into the transition "From Graduate Student to Young Professional".

A novel antibiotic class targeting the lipopolysaccharide transporter - Nature A tethered macrocyclic peptide antibiotic class described here—which shows potent antibacterial activity against carbapenem-resistant Acinetobacter baumannii—blocks the transport of bacterial lipopoly...

Insightful lecture by Hayley Binch at #MedChemFrontiers24. She talked about "Polarities in Drug Discovery" and how they can be combined into successful drug discovery campaigns. Great to see her highlight their antibiotic work against A. baumannii. doi.org/10.1038/s415...

Native Mass Spectrometry‐Guided Screening Identifies Hit Fragments for HOP‐HSP90 PPI Inhibition** We sought to demonstrate the combined utility of native mass spectrometry (MS), and fragment-based drug discovery as a viable means for identifying protein-protein interaction (PPI) inhibitors. Here ...

Interesting talk by Clint Veale at #MedChemFrontiers24. He talked about his group's work on new methods for native mass spectrometry to study transient protein-protein interactions and to find modulators for them on the main example of HSP90 complexes. doi.org/10.1002/cbic...

Bicyclic β‐Sheet Mimetics that Target the Transcriptional Coactivator β‐Catenin and Inhibit Wnt Signaling Starting from a 52 amino acid protein binding epitope, a bicyclic β-hairpin structure was developed to bind the transcriptional coactivator β-catenin. Our structure-based design approach was supporte....

Very interesting talk by Tom Grossmann at #MedChemFrontiers24. He talked about his group's exciting work on peptidomimetics including (bi)cyclic peptides for addressing challenging protein targets including β-catenin. doi.org/10.1002/anie...

Great talk by Luc Brunsveld at #MedChemFrontiers24. Targeting disordered proteins by the covalent stabilization of their interaction with 14-3-3 proteins. Cool to see him highlight collaborations with Peter Cossar, Christian Ottmann and Michelle Arkin. doi.org/10.1021/jacs...

What Makes a Great Medicinal Chemist? A Personal Perspective Although it is extremely challenging to invent new medicines, I have observed that certain behaviors seem to be commonly found among successful medicinal chemists. Those who exhibit most of these char...

Insightful opening lecture by Mark Murcko at #MedChemFrontiers24. He talked about some overarching, transferable lessons for successfully doing drug discovery and being a good medicinal chemist. doi.org/10.1021/acs....

Very excited to be at the #MedChemFrontiers24 meeting of the EFMC in Utrecht. Looking forward to a full week of exciting science including talks by Seino Jongkees, Luc Brunsveld, Tom Grossmann, Clint Veale and Lyn Jones.