ideasIdea
An open map of which cancer proteins any drug can stick to
Most cancer proteins have never been tested to see whether a small molecule can attach to them at all. A public map of what is chemically reachable would tell the field where to aim.
Activity-based protein profiling with covalent fragment libraries can measure ligandable sites across thousands of proteins in cancer cell lysates and live cells. Existing datasets are partial and largely proprietary. A precompetitive atlas covering the cysteine, lysine and tyrosine proteomes across 50 cancer models, published openly with hit compounds deposited, would convert 'undruggable' from an assertion into a measurement.
Hypothesis
Systematic covalent fragment profiling identifies ligandable sites on at least 200 proteins currently classified as undruggable, and at least ten of these yield functional chemical probes within three years.
Rationale
The approach found the ligandable site that became the KRAS G12C drug class. Coverage, not concept, is the limiting factor, and the cost per protein falls sharply with shared infrastructure.
What would test it
Fund two chemoproteomics centres for three years with mandated quarterly public data release; count new ligandable sites and probes independently reproduced by a third laboratory.
Maturity
preclinical evidence
Who has to act
philanthropy
Cost to try
Medium ($1M to $50M)
Years to first evidence
4
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.
- Preclinical results do not reproduce · Fewer than half of landmark cancer biology findings reproduce when someone else tries.