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Molecular glues that break the MYC-MAX partnership

MYC drives many cancers but has no drug because it has no pocket. A glue-like molecule that jams its required partner protein could switch it off.

MYC must dimerise with MAX to bind DNA. Rather than seeking an inhibitor pocket on MYC, a molecular glue or bifunctional degrader could stabilise a non-productive MYC conformation or recruit an E3 ligase to the MYC-MAX interface. Precedent for gluing intrinsically disordered proteins now exists (for example the recruitment of transcription factors to cereblon by aryl sulfonamides and CELMoD-class agents).

Hypothesis
A compound that reduces nuclear MYC protein by 80 percent for 24 hours produces tumour regression in MYC-amplified xenografts with tolerable effects on regenerating tissues.
Rationale
Degradation avoids the need for a binding pocket, which is why glues have already drugged the previously intractable IKZF1/3 and RBM39. MYC has a short half-life, so partial degradation should have a large functional effect.
What would test it
Chemoproteomic glue screening against MYC-MAX in a MYC-amplified line with degradation readout, followed by tolerability studies in mouse models where MYC is required for gut and marrow renewal.
Maturity
preclinical evidence
Who has to act
industry
Cost to try
Large (over $50M)
Years to first evidence
8
Bottlenecks it attacks
  • The undruggable drivers · The proteins that drive most cancers, such as MYC, mutant p53 and most RAS variants, still have no good drug.

Connected

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Pages like this

not linked directly; found by shared links

technologies

2
AI-driven drug & target discoveryPROTACs & molecular glues (targeted protein degradation)

companies

3
C4 TherapeuticsKymera TherapeuticsMonte Rosa Therapeutics

terms

1
Oncogene addiction

bottlenecks

1
The undruggable drivers