Molecular Glue ⚛️

Welcome to Alternate Universe!

In today’s edition:

• Molecular glue - drugging the undruggable ⚛️

• Job opportunities at recently funded European startups 👇

• This woman will name your baby for the low price of $30k 👶

The Crux 🔴

A few months ago, as I was scrolling through the endless AI slop that LinkedIn has now become, something caught my eye.

The cover of the latest issue of Science magazine featuring a term that sounded straight out of sci-fi.

Molecular glue.

I had to dig deeper.

You already know what time it is.

🐰🕳️⌚

What? 🧐

Molecular glues are a new type of drug class designed not only to block a disease-causing protein but to help the cell eliminate the protein entirely.

A molecular glue works a bit like a chemical matchmaker. It encourages a faulty protein to latch onto the cell’s natural waste-disposal machinery (an enzyme called an E3 ubiquitin ligase). Once in contact, the enzyme tags the protein with ubiquitin, a signal that sends it to the cell’s recycling unit for destruction.

This approach is especially powerful for proteins that lack the usual “pockets” needed for classic drug binding. By forcing these proteins into contact with the disposal system, molecular glues open the door to treating targets that were previously considered undruggable.

Molecular glues belong to the broader field of Targeted Protein Degradation (TPD), which focuses on clearing out harmful proteins rather than merely silencing them. TPD uses the cell’s own clean-up systems to selectively eliminate proteins involved in diseases such as cancer, neurodegeneration, or immune disorders.

The best-known TPD drugs are PROTACs (proteolysis-targeting chimeras). These are larger, two-armed molecules that simultaneously bind the target protein and the E3 ligase to bring them together. Molecular glues achieve a similar effect with a simpler, single-arm design that subtly reshapes the enzyme to grip the target. Together with lysosome- and autophagy-based approaches that reach membrane or extracellular proteins,

Why does it matter? 🙅‍♀️

In immunology alone, about 160 million people live with chronic inflammatory diseases, yet only 3 percent receive advanced systemic therapies. Most of these treatments are injectable biologics that generate over $100 billion a year in sales, leaving roughly 97 percent of patients underserved or untreated.

Despite decades of progress in drug discovery, around 80 percent of the human proteome remains “undruggable” with conventional small molecules because many disease-driving proteins lack the deep binding pockets that traditional inhibitors need. Targeted protein degraders and molecular glues can go after these previously inaccessible proteins, unlocking opportunities not just in immunology but also in cancer and neurodegeneration.

The potential impact is significant.

Event-driven degradation often enables lower and less frequent dosing, and early proof points already exist: lenalidomide and pomalidomide, used in multiple myeloma, were later recognized as molecular glues, while first-generation PROTACs such as ARV-471 for breast cancer are advancing through clinical trials. These successes point to a pipeline that could reshape treatment for millions who currently lack effective options.

Challenges ⛔

Despite the excitement surrounding targeted protein degradation, bringing these drugs to routine clinical use remains challenging.

A core hurdle is how the medicines behave in the body. Many degraders do not easily reach the right tissues or enter cells efficiently, especially if they are large or complex molecules. Unlike traditional drugs that block a protein’s activity, degraders remove the protein entirely, so their effects can last long after the drug has left the bloodstream. That makes it harder to fine-tune the dose and raises the risk of side effects.

Safety and delivery remain central challenges. Eliminating a protein can disrupt normal cell functions if the target is also important in healthy tissues, and imperfect selectivity can damage unrelated proteins. Cancer cells and other targets can also develop resistance by mutating the protein or reducing the activity of the enzymes that carry out degradation.

On top of the biology, there are practical issues such as relying on only a few available E3 ligases to trigger degradation, and the manufacturing complexity of newer hybrid drug formats. These barriers need to be solved before the full promise of this technology can be realised.

Investment Implications 🤑

As TPD and molecular glue technologies mature, the biotech players that secure the right licenses, partnerships, and pipeline breadth are likely to outperform those that remain isolated. Large pharma is already stepping in through licensing, acquisitions, and collaborations, and some of these agreements involve full integration of platform rights rather than simple option deals. Smaller biotechs with novel tech could become prime acquisition or licensing targets, giving investors the chance to capture upside.

Among the public names, Kymera stands out for its strong roster of partnerships and a pipeline that spans both immunology and oncology. Deals with Gilead, Sanofi, and Vertex validate its approach and provide non-dilutive funding. Arvinas also has multiple Phase 1-3 programs across different indications, providing a diversified pipeline. However, these are still small-cap biotech stocks whose stock price can swing like crazy on clinical updates.

Not for the faint-hearted.

Dig Deeper ⛏️

• Targeted protein degradation: current molecular targets, localization, and strategies

• Understanding targeted protein degradation

• PROTAC targeted protein degraders: the past is prologue

P.S. Liking this issue? Forward to a friend 🧑‍🤝‍🧑

Headhunted 🦅

Recently funded private companies need talent! Scout jobs at recently funded European startups, ahead of your competition. 💪

1. Auterion 🇨🇭 - The US-Swiss producer of autonomous defense systems has raised $130m in a Series B round. Multiple engineering, operations and sales roles open (link)

2. WeTravel 🇳🇱 - The online travel platform has raised $92m in fresh funding. Commercial, compliance, and CX positions (link)

3. Zilo 🇬🇧 - The asset management software startup has raised £20m in a new funding round. Multiple roles open (link)

4. Defacto 🇫🇷 - The French fintech has raised €16 million in a Series B. Hiring engineers (link)

5. Cylib 🇩🇪 - The German battery recycling startup has been awarded a €26m grant. Finance, engineering & operations positions open (link)

Interestingness📔

• Investing in domain names 👀

• The AI drug discovery activity is still strong 💊

• Are we in an AI bubble? 🫧

• This woman will name your baby for the low price of $30k 👶

📚 New to investing? Grab a PDF copy of my ebook here.

As always, the financial disclaimer!

This is not investment advice. I am not a financial advisor. Make sure to conduct your thorough research before purchasing or selling financial products.