pipeline-gap-target

AKR1C3 is an enzyme that makes potent male hormones and that some cancers carry in large amounts. Rather than blocking it, prodrugs use it as a key: they stay inactive until AKR1C3 inside a tumour cell converts them into a DNA-damaging drug.

ALC1 loosens packed DNA at sites of damage so it can be repaired. Cancers that already lack the BRCA repair route, such as some breast and ovarian cancers, lean on it, and losing it made such cells far more sensitive to PARP inhibitors in the laboratory; an ALC1 inhibitor is in early trials.

CDC7 is the kinase that switches on the starting points of DNA copying in each cell cycle. Cancer cells starved of it attempt to copy their DNA anyway and die, while normal cells pause; a CDC7 inhibitor is in trials for acute myeloid leukaemia and myelodysplastic syndromes.

CDK11 is an enzyme that helps the cell's splicing machinery cut and join its gene messages correctly. Blocking it leaves messages unfinished; one CDK11 inhibitor is in preclinical development.

DHODH is an enzyme cells need to make pyrimidines, the building blocks of DNA and RNA. Blocking it pushed immature leukaemia cells to mature in mouse studies, and a DHODH inhibitor is in an early trial in solid tumours and lymphoma.

EP4 is one of the receptors for prostaglandin E2, a signal many tumours release that quietens the immune cells around them. EP4 blockers are meant to lift that suppression, and two are in early trials, one with pembrolizumab.

GPR65 is a sensor on immune cells that detects acidity. Tumours are often acidic, and the idea behind blocking GPR65 is to stop that acidity from turning nearby immune cells into ones that help the tumour; a GPR65 inhibitor is in an early trial.

HPK1 is a brake inside immune cells: it dampens a T cell's response once the cell has recognised its target. Blocking it is meant to let T cells attack a tumour harder, and an HPK1 inhibitor is in an early trial, alone and with a checkpoint antibody.

KIF18A is a motor protein that keeps chromosomes lined up during cell division. Tumour cells with unstable chromosome numbers depend on it while normal cells largely do not, which is the case for the KIF18A inhibitors now in early trials.

LSD1 is an enzyme that removes small chemical tags from the proteins DNA is wound around, switching genes off or on. Many cancers carry a lot of it and it helps keep leukaemia cells immature; several LSD1 inhibitors have been tested in blood cancers and solid tumours.

MAO-A is an enzyme best known for breaking down serotonin and other signalling chemicals in the brain; medicines called MAO inhibitors, used for some neurological disorders, block it. Aggressive prostate cancers carry more of it, and a MAO-A inhibitor designed to stay out of the brain is in an early prostate cancer trial.

PARG clears away the poly(ADP-ribose) chains that PARP enzymes lay down at damaged DNA. Blocking it is meant to deepen the replication stress some cancers already live with, as a partner or alternative to PARP inhibitors; two PARG inhibitors are in trials.

PLK4 is the enzyme that starts the copying of the centrosome, the structure that organises a dividing cell's spindle. Cancers with extra copies of the TRIM37 gene cannot divide properly once PLK4 is blocked, and two PLK4 inhibitors are in early trials.

RIPK2 relays alarm signals from the NOD1 and NOD2 sensors that detect bacteria, switching on inflammation. It has been proposed as a cancer target both for its effects on immune cells and, in prostate cancer, for helping tumours spread; a RIPK2 inhibitor is in an early melanoma trial.