ideasIdea

Design protein degraders small enough to get into the brain

New drugs that destroy cancer proteins are usually too big to enter the brain. Making much smaller versions could bring this approach to brain tumours.

Bifunctional degraders typically exceed the size and polarity limits for passive brain entry, whereas molecular glues such as the thalidomide analogues are small and drug-like, and brain-penetrant glue degraders have been reported in neuroscience programmes. Applying glue chemistry to brain tumour dependencies, including transcription factors and fusion oncoproteins, would open targets that current chemistry cannot reach in the brain.

Hypothesis

Molecular glue degraders can be optimised to an unbound brain-to-plasma ratio above 0.3 while retaining degradation potency, enabling degradation of a central nervous system tumour dependency in vivo.

Rationale

Glue degraders are small enough to obey central nervous system drug-likeness rules, unlike classical bifunctional degraders, and degradation is catalytic so lower brain concentrations may suffice. Neuroscience programmes have already demonstrated brain-penetrant glue chemistry.

What would test it

A medicinal chemistry campaign with brain exposure as a primary optimisation parameter against one glioma dependency, reporting the brain-to-plasma ratio and in vivo target degradation in tumour tissue.

Maturity

preclinical evidence

Who has to act

industry

Cost to try

Medium ($1M to $50M)

Years to first evidence

Bottlenecks it attacks

The brain: barrier and sanctuary · Most drugs cannot cross into the brain, so brain tumours and brain metastases lag every other site.
The undruggable drivers · The proteins that drive most cancers, such as MYC, mutant p53 and most RAS variants, still have no good drug.

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Design protein degraders small enough to get into the brain

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bottlenecks