wave5-target

ABL1 is the kinase half of the BCR::ABL1 fusion that causes chronic myeloid leukaemia. The CML drugs bind the ABL1 kinase domain, most in its ATP pocket and asciminib in a separate pocket that locks it shut.

ACVR1 (ALK2) is the receptor that raises hepcidin, the hormone that hides iron from the bone marrow. Momelotinib and pacritinib block it as well as JAK2, which is why they improve, rather than worsen, the low red-cell counts of myelofibrosis.

B7-H4 is a checkpoint-like protein that many breast, ovarian and endometrial tumours carry on their surface. Antibody-drug conjugates such as puxitatug samrotecan and HS-20089 use it as a docking site to deliver a chemotherapy payload.

BAX is the protein that opens the mitochondria to start cell death. BCL-2 keeps it in check in leukaemia cells; venetoclax and sonrotoclax free it, so the mitochondria leak cytochrome c and the cell dies.

BIM is a pro-death protein that leukaemia cells keep clamped by BCL-2. Venetoclax and sonrotoclax are BH3 mimetics: they copy the part of BIM that binds BCL-2, so BIM is released, the mitochondria leak and the cell dies.

BRD4 is a reader protein that docks on acetylated DNA packaging and pulls in the machinery that switches growth genes such as MYC on. BET inhibitors such as pelabresib and ZEN-3694 block that docking; in NUT carcinoma the cancer's own driver is a BRD4 fusion.

4-1BB is a switch on activated T cells that makes them live longer and kill better. Rather than press it everywhere, new bispecific antibodies press it only on T cells that are already touching a tumour cell marked by PD-L1 or HER2.

CD28 is the second signal a T cell needs before it attacks. Many CAR-T cells carry a piece of CD28 inside them to fire harder, ipilimumab works by stopping CTLA-4 from hogging CD28's partners, and a new bispecific antibody presses CD28 directly on T cells that are already bound to prostate cancer cells.

B7-1 is a molecule on antigen-presenting cells that gives T cells their go signal through CD28, but it also feeds the CTLA-4 brake and can pair with PD-L1. Anti-PD-L1 antibodies such as sugemalimab and adebrelimab are built to stop PD-L1 binding both PD-1 and B7-1.

FAK is the kinase that tells a cell it is anchored to its surroundings, letting it survive, move and resist drugs. Defactinib, given with the RAF/MEK inhibitor avutometinib, removes that escape route in low-grade serous ovarian cancer; other FAK inhibitors are in trials in meningioma and solid tumours.

HIF-1α is the sensor that lets a tumour cope with low oxygen by switching on blood-vessel growth and sugar burning. It has no direct drug yet; belzutifan hits its sibling HIF-2α, and the mTOR inhibitor temsirolimus lowers HIF-1α levels indirectly.

HLA-A is the molecule that holds up short pieces of a cell's proteins for T cells to inspect. Engineered T-cell receptor therapies such as tebentafusp and afami-cel only work in people with the HLA-A*02 variant, because the receptor recognises the tumour peptide sitting in that particular groove.

HOXA9 is an embryonic growth gene that some leukaemias keep switched on so their cells never mature. Menin inhibitors such as revumenib and ziftomenib do not touch HOXA9 itself; they pull menin off the DNA so the gene switches off and the cells grow up.

IDO1 is an enzyme tumours use to burn up tryptophan, starving T cells and producing by-products that switch them off. Epacadostat blocked it but its programme ended in failure; the IO102-IO103 vaccine instead teaches T cells to attack the IDO1-expressing cells themselves.

Ikaros is a transcription factor that myeloma cells depend on. Lenalidomide, pomalidomide and the newer CELMoDs work by gluing Ikaros to the cell's disposal machinery so it is destroyed, which kills the plasma cell and wakes up T cells.

Aiolos is Ikaros' partner transcription factor in B cells and plasma cells. The myeloma drugs lenalidomide, pomalidomide and golcadomide destroy Aiolos and Ikaros together by rerouting them to the cell's protein-disposal system.

IRF4 is a master transcription factor of plasma cells and a protein myeloma cells cannot do without. Lenalidomide and its successors lower IRF4 by destroying the two factors, Ikaros and Aiolos, that keep it switched on.

JAK1 is one of the kinases that pass cytokine and interferon signals inside immune and blood cells. Ruxolitinib and momelotinib block JAK1 together with JAK2 to calm the inflammation of myelofibrosis; golidocitinib is the first JAK1-only inhibitor approved for a cancer, in peripheral T-cell lymphoma.

MEIS1 is HOXA9's partner in keeping leukaemia cells immature. The two are switched on together in KMT2A-rearranged and NPM1-mutant leukaemia, and switched off together when a menin inhibitor works.

MPL is the receptor that tells the bone marrow to make platelets. Romiplostim and eltrombopag switch it on to raise platelet counts; in some myeloproliferative neoplasms a mutant partner protein, calreticulin, grips it and keeps it on.

NF1 makes neurofibromin, the protein that switches RAS off. People born with one faulty copy develop neurofibromatosis type 1, whose plexiform neurofibromas are now treated with the MEK inhibitors selumetinib and mirdametinib, which cut the RAS signal one step down.

NRAS is one of the three RAS switch proteins that pass growth signals into the cell. When a mutation jams it on, as in a share of melanomas, the cell keeps dividing; today's drugs reach it indirectly through MEK or RAF, and pan-RAS inhibitors that bind the active form are in trials.

PTCH1 is the brake on the hedgehog growth pathway. When it is lost, as in nearly all basal cell carcinomas and in Gorlin syndrome, the pathway runs unchecked; vismodegib and sonidegib put the brake back one step down, at smoothened.

SHP2 is an enzyme that sits between growth-factor receptors and RAS and keeps the RAS signal flowing. Blocking it removes the route by which KRAS-driven tumours bounce back from a KRAS inhibitor, which is why SHP2 inhibitors are being paired with KRAS G12C drugs.

STAT5 is the messenger that carries growth signals from FLT3, JAK2 and BCR::ABL1 into the nucleus and switches on survival genes in leukaemia cells. No drug hits STAT5 directly yet; the FLT3 and ABL inhibitors work by cutting off the signal above it.

TET2 is an enzyme that helps erase methyl marks from DNA so genes can be switched back on. Losing it is one of the commonest first steps toward blood cancer; mutant IDH blocks it indirectly, which is part of how ivosidenib works when it restores normal maturation.