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Author: Jean-Claude Muller, 穆卓Executive Editor at BtoBioInnovation  jcm9144@gmail.com

SPECIAL REPORT 24.09

Medicinal Chemistry: A great past, an underestimated future

The following testimonial was delivered by Jean-Claude Muller, former President (1996-1998) of the European Federation for Medicinal chemistry and Chemical biology (EFMC) at the Opening Ceremony of the XXVIII EFMC-International Symposium on Medicinal Chemistry (ISMC) in Rome (Italy) on September 1, 2024.

Dear Fellow Chemists

Ever since I have been involved in drug discovery, I have heard “Do we still need medicinal chemists?” or even worse “We don’t need medicinal chemists anymore”.  And I guess most of you have, at some time, been exposed to a similar message delivered by CEOs, consultants, gurus and more recently by so called influencers.

When, on September 1, 1974, 50 years ago as of today, I started my career in the biopharmaceutical industry the buzz word was peptides. “They are more potent and more specific than small molecules, they are easily designed and can be produced by programmed machines”. They did not make the cut at the time and only recently have they produced approved drugs of major importance such as the GLP-1 agonists. Then came recombinant proteins which would wipe out the necessity to produce new small molecules. This technology produced great new drugs, but it did not replace small molecules. When, at the same time, molecular modelling made its way, I heard that this approach would be so accurate that one would just need to produce a handful of molecules to design a perfect drug. No need of armies of medicinal chemists anymore. We all know the outcome. Just a few years later we saw the emergence of the humanized antibodies, the holy grail to cure cancer and inflammatory diseases. Again, many products based on this technology became breakthrough drugs, but small molecules were also highly competitive in these areas. I could go on like this with gene therapy, cellular therapy and now Artificial Intelligence with its strong and extravagant claim to definitively eliminate Medicinal Chemistry.

Let me present a few data to illustrate my point.

Over the last twenty years, roughly 60-65% of all the new approved drugs in the world were small molecules. I have already identified 15 out 23 in 2024.

The oncology domain is very interesting to analyse over these last twenty years. There is no doubt that major improvements have been proposed to patients and many were biologics.

But do you know how many small molecules have done a similar job over the same period?  103 in 30 different indications.

How many in the last 10 years? 66.

How many in the last 18 months? 16 +2 radioligands.

A very impressive performance delivered by medicinal chemists to help and relieve millions of cancer patients.

The recent approval of vorasidenib, an IDH1/2 dual inhibitor, the first major treatment of low-grade glioma, is a perfect example of what medicinal chemistry can still deliver today.

At the beginning of this year at the JPMorgan Health conference, the largest business conference in the world, Antibody-drug conjugates (ADCs) were claimed to be the “hottest ticket” of the year. What a beautiful example of strong collaboration between medicinal chemistry and modern biology to produce a hybrid structure that combines biologics with well-defined chemical entities such as linkers and cytotoxic drugs.

The long-neglected field of antiviral has been a playground where medicinal chemistry has made miracles. AIDS patients have now access to lecanapavir, a capside inhibitor, which has a 100% efficacy for the HIV prevention when given subcutaneously twice a year.

At this stage, let me make a very strong statement: Without medicinal chemistry, 40 years after the outbreak of the disease, HIV patients would still have no treatment.

What is still in front of you in medicinal chemistry in the years to come?  A lot, not just an easy stride, but an exciting journey. A few recent examples to try to convince you.

Peptides GLP-1 agonists are going to be replaced by small molecular entities (SMEs) which have already proven to be effective in late stage clinical settings. Several laboratories are designing small molecules to become the next generation checkpoint inhibitors. A first oral small molecule inhibiting PCSK9 has shown strong anti-cholesterol activity. I am aware of programs where SMEs are being designed to replace any type of antibody. Barely conceivable a few years ago such achievements are now just around the corner thanks to skilled innovative medicinal chemists such as you here in this audience.

The following areas are still in strong need for better treatments: Antivirals, antibiotics, neurological diseases, chronic inflammation, pancreatic cancer, glioblastoma and the 6,000 to 8,000 rare diseases. There is also a need for agents that counteract resistance pathways for antibiotics and tumour microenvironment and for new vectors and shuttles to allow better penetration of specific organs in particular the CNS.

Third generation ADCs, radiopharmaceuticals (where a radioactive chemical is linked to a cell-targeting molecule), protein degraders and other molecules designed by medicinal chemists are already showing signs of potential future success.

Let me finish with one recommendation based on my own experience.

Try to understand the issue and problems of the biology of your domain and propose and find a chemical solution. You may not get the glory and the reward of the success, but you will gain the respect of your peers for your contribution.

In conclusion I would reemphasise:

Do not listen or believe messages from consultants, gurus and influencers. I am the first one to admit that most of the already mentioned new technologies have proven successful in delivering useful new drugs, but none of them has replaced medicinal chemistry. Artificial Intelligence (AI), which is now presented as a new panacea, will just be the same story, there is no doubt that AI will have a future in drug discovery and that it will become another very useful tool in the toolbox. What I saw over the last thirty years is straightforward: All the new technologies have obliged medicinal chemists to tackle more difficult issues and substantially improve their performance and the quality of their output. I am confident that in twenty years from now, biopharmaceutical R&D organisations will still strongly rely on medicinal chemistry, on chemical biology and on skilled medicinal chemists to discover and develop new innovative drugs.

I wish you a great ISMC meeting here in Rome and lots of successes in your ongoing projects.

Rome, September 1, 2024.

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