Summary of the ACSMEDI-EFMC Medicinal Chemistry Frontiers in May 2025

In May, we had a great time exhibiting at the ACSMEDI-EFMC Medicinal Chemistry Frontiers in Chicago. We enjoyed catching up with clients to discuss how our medicinal chemistry consultants can lead/advise on projects and how our MCPairs software can help chemists choose which compounds to make next. We also attended the diverse range of talks from industry and academic scientists and will highlight a few that we found interesting here (references included where found).

The BEan

The Bean – Chicago

The event kicked off with an insightful talk from Dr Ingo Hartung from Merck. He described the use of Merck’s AI platform, AIDDISON, to utilise data for compound design (1); in particular how they were able to guide the design of PROTACS using predictions of mouse oral bioavailability. He also introduced a new PROTACS concept: the PROxAb Shuttle, which involves binding antibody domains with PROTACS to generate bispecific fusion proteins that can target specific cells and induce cell death (2). Dr Hartung also dedicated a slide to highlight other significant medicinal chemistry feats in recent times, including a shoutout to Revolution Medicine’s macrocyclic KRAS compound, RMC-9805 (3), which he described as “one of the most impressive pieces of medicinal chemistry I’ve seen”. MedChemica had the pleasure of contributing to this program, so it was great to see the final compound presented on the big screen.

RMC 9805

We also enjoyed a talk by Dr Aaron Coffin from Atavistik, who described their work designing allosteric modulators of AKT1E17K using their Atavistik Metabolite Proprietary Screening (AMPS) platform (4). In their previous careers at AstraZeneca, the team at MedChemica contributed to the design of Capivasertib a pan-AKT inhibitor that was recently approved for the treatment of HER2-negative breast cancer (5). The idea presented by Dr Coffin was that an allosteric AKT1 modulator would have improved selectivity over the other AKT kinases, reducing some of the known side effects of pan-AKT inhibitors, in particular hyperglycemia. The resulting compound was selective, did not cause hyperglycemia, and showed tumour regression in a PDX model but was not progressed further. It was great to see the proof of concept and the introduction of an AKT1-selective tool compound.

It was also really interesting to hear a talk by Dr Ben Cons from Astex on the discovery of ASTX295 (6), a bone-marrow sparing MDM2 antagonist. The talk highlighted issues with current MDM2 antagonists causing bone marrow toxicity and hypothesised that a short-acting compound would be less toxic. A key goal in lead optimisation was to hit a half life sweet spot of 4-8 hours, as opposed to the current MDM2 antagonists that have half lives of > 12 hours. The project used structure-based drug discovery to improve binding and cell-potency and found three compound series. In the end, it was an acidic compound, ASTX295, that had the optimum profile and has now completed a phase 1 trial.

ASTX295

Another great talk was given by Dr Jing He from Relay Therapeutics, on using computational models to guide the design of RLY-2139 (7), a CDK2-selective compound for the treatment of breast cancer. Four different modelling approaches were used. Firstly, FEP was found to be reasonably predictive of CDK1 and CDK2 potency but could not predict the selectivity when combined. Secondly, MD simulations found that selective CDK2 inhibitors induced more folding of the p-loop. Next, a H-bond network was found to be uniquely present in CDK2 and the stabilisation of this network was linked to selective inhibition. Finally, a dynamics-based ML model, where 500 ligand-CDK1/CDK2 simulations were used as training data, was found to be very predictive of CDK2 selectivity. The talk demonstrated how computational modelling can guide rational medicinal chemistry design, as well as the importance of developing bespoke modelling techniques based on the specific system being studied.

We also enjoyed Katerina Leftheris’ talk on peptide and macrocycle drug discovery, which introduced the concept of protein-like polymers (PLPs) as intracellular delivery systems for peptides. A PLP is composed of a hydrophobic polymer backbone with therapeutic peptide “bristles”. They are observed to undergo passive permeation into cells and are even seen to penetrate the blood brain barrier. Computational modelling of these systems suggests the hydrophobic backbone forms a compact structure in water but opens up to span a lipid bilayer, with the peptide bristles located in the polar head region/ solvent. Not only do PLPs improve the permeability of therapeutic peptides, they are also seen to increase their binding potency. Dr Leftheris postulated that the improved binding was driven by a reduced koff rate. Apologies we could not find an appropriate reference for this material.

Finally, we want to highlight the inspiring, career-spanning talk given by Dr Wendy Young. She summarised projects including her contributions to the chemotherapy Alimta, Tryptase inhibitors for asthma, and work targeting Factor Xa for pulmonary embolisms and DVT. The two key quotes we took from the first half of her talk were:

 “Challenge the dogma – ask questions, check the data” and

 “The power of med chem is that really small changes can have a big effect”.

These messages are central to the work we do with Matched Molecular Pair Analysis at MedChemica. MMPA is critical for challenging the dogma, since it ensures that we check the data behind our beliefs that certain medicinal chemistry transformations cause certain effects. It was great to see Dr Young present a Matched Molecular Pair plot showing the effect of transforming a 1-fluoro-benzene to a 2-pyridine on metabolic stability of a chemical series (8). Using our Transformation Searcher tool in MCPairs we are able to search public data that corroborates Dr Young’s observation and display it in a Matched Pair plot similar to that presented in the talk.

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The second half of Dr Young’s talk focused on her work as an advocate for women’s healthcare and women in medicinal chemistry. Historically, medicinal chemistry has been a male-dominated field and this is reflected in the drugs that we see come to market (9). According to Dr Young, there have been 617 FDA approved drugs in the last 15 years but only 46 of these were specific to women. Dr Young drew attention to the issues that women face when receiving healthcare, including their symptoms being minimised. This is especially true for ovarian cancer, which is often called a “silent killer” because cases were believed to be symptomless. Recent research into the experiences of survivors of ovarian cancer has debunked this belief with countless stories from women who reported bloating and pain but were dismissed by their doctors (10). Dr Young finished her talk with a call to action to those working in drug discovery: encourage research of targets linked to female diseases – this is the best way to improve the experiences of women receiving healthcare and to address the inequalities that persist in medicine. Thank you to Dr Young for her inspiring lecture and food for thought.

 

By Dr Lauren Reid – Computational Chemist / Developer @MedChemica Ltd