The undruggable drivers

Nearly all cancer drugs are found by killing fast-growing cells. Sleeping cells survive them. A screen designed around dormant cells would find a different class of drug.

Governments promised in advance to buy vaccines that did not yet exist, and they got made. The same promise could be made for a drug against a target everyone has given up on.

No single company will spend a decade on a target that might be impossible. A shared, openly published effort across the twenty hardest targets spreads that risk.

For each cancer-causing mutation, find every gene the cancer cell newly depends on, in every tissue, so that even undruggable drivers get druggable partners.

For each drug target, show how many programmes have been tried against it and how many failed, so new teams know what they are up against.

MYC, fusion oncoproteins and transcription factors have shapeless, flexible regions that drugs cannot grip. Deep-learning protein design tools such as RFdiffusion may be able to invent binders that clamp them, for use as degradation handles, intrabodies or targeting domains for CAR and bispecific therapies rather than as drugs themselves.

Cancer's most important drivers, such as MYC and mutant p53, cannot be blocked with normal drugs. Pool effort and share results openly to build molecules that destroy them instead.

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.

Companies and public funders would pool money and scientists to crack the hardest cancer proteins, such as MYC and mutant p53, sharing everything openly until there is a real drug candidate, then competing on the final product.

Cells chop up their internal proteins and display the pieces on their surface. That means even undruggable proteins inside the cell can be attacked from outside by the immune system.

Tumours often lose one of a pair of near-identical genes. They then depend entirely on the remaining copy, which a drug can block, killing only the cancer.

Some cancer-driving proteins gather into droplet-like blobs inside the nucleus to switch genes on. Drugs that dissolve those blobs might switch the cancer programme off.

One RAS mutation can now be drugged because it offers a reactive handle. Most RAS mutations do not, so new chemistry is needed to grab other amino acids.

Some faulty p53 proteins do not just stop protecting the cell; they actively help the cancer. Removing them entirely may be easier than fixing them.

Some sarcomas in children are caused by two genes fused into one abnormal protein. That protein is the whole disease, but no drug binds it. Destroying it instead of blocking it could work.

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.

In advanced prostate cancer the AR-V7 splice variant of the androgen receptor lacks the ligand-binding domain that enzalutamide and abiraterone act on, and its presence predicts resistance. A degrader or N-terminal binder that removes the whole protein, variants included, would still work; AR-V7 is already measurable in circulating tumour cells.

Some cancer proteins sit on the cell surface or float outside cells, where protein-destroying drugs cannot reach. A different trick can drag them inside to be broken down.

Some harmless bacteria naturally grow in the low-oxygen core of tumours. Engineering them to produce immune-activating drugs turns them into tiny factories inside the tumour.

One faulty version of the p53 guardian protein can now be repaired by a drug that plugs a hole in it. Systematically hunting for similar holes in other faulty versions could help far more patients.

Protein-destroying drugs work by hijacking cellular waste-disposal machines. Using a machine that is mostly present in cancer cells would make these drugs safer.

Deliver genetic instructions so the cancer cell itself manufactures a molecule that traps its driver protein inside the cell.

Undruggable cancer proteins such as beta-catenin, MYC and KRAS act through broad flat protein-protein interfaces that small pills cannot cover. Ring-shaped macrocyclic peptides can, some series are cell-permeable, and mRNA display can screen trillions of candidates; the proposal is a focused campaign with open publication of permeability rules.

Pay a fixed prize, of tens of millions, to the first team to show that a completely new way of attacking cancer works in patients, so that the riskiest early bets are rewarded even before a product exists.

MYC is a cancer-driving transcription factor with no drug because it has no binding pocket. A molecular glue or degrader that jams its required partner MAX, or recruits an E3 ligase to the MYC-MAX interface, could switch it off; gluing disordered proteins now has precedent from cereblon-binding drugs.

A decoy protein can bind MYC's partner and block it. Delivering the instructions for that decoy as mRNA in a fat nanoparticle avoids having to inject the protein itself.

Small-cell lung cancer has had two real advances in twenty-five years. It is probably four diseases being tested as one, in separate small trials that each need their own control group.

The US government already runs a small programme that turns academic cancer discoveries into drugs ready for human trials. Scale it up tenfold and copy it in other countries.

Molecular glue degraders make one protein destroy another, but thalidomide analogues and indisulam were found by luck. A systematic screen of chemical libraries against genetically diverse cancer cell lines, published as an open atlas, would map which of the roughly 600 human E3 ligases can be redirected and against which targets.

If the protein cannot be drugged, target the message that makes it. Small molecules can now recognise folded shapes in RNA and recruit an enzyme that chops it up.

Cancers driven by MYC need to make proteins at an unusually fast rate. Slowing the cell's protein factory hits them harder than it hits normal cells.

Instead of blocking a cancer protein, add a chemical off-switch to its gene so the cell stops making it. Early versions of this tool are being tested in other diseases.

Cells have an enzyme, PP2A, that removes the growth signals cancer relies on. Cancers switch it off. Drugs that switch it back on are an unusual and largely untried approach.

Chromosomally unstable, often whole-genome-doubled tumours survive constant chromosome mistakes by depending on the motor protein KIF18A, which diploid cells do not need. Blocking it kills unstable cancer cells while sparing normal ones; inhibitors are in early trials in ovarian and other cancers.

Drugs that destroy proteins can hit healthy cells too. Attaching them to an antibody that only docks onto tumour cells would keep them where they are needed.

The brain imports iron through the transferrin receptor. Antibody shuttle domains that bind that receptor raise brain exposure roughly ten to fifty-fold in primates and are already used in clinical Alzheimer's antibodies; the same engineering could carry antibody-drug conjugates or T-cell engagers to brain metastases.

In a minority of men, prostate cancer escapes hormone drugs by becoming a different kind of cell that no longer needs the androgen receptor. By the time a biopsy shows it, the treatment options are almost gone. The genetic changes that allow the switch are detectable years earlier, and nobody is looking for them.

Cancers with faulty DNA proof-reading depend on one particular unwinding enzyme to survive. Blocking it kills them and spares normal cells.