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Every dividing cell passes three gates and keeps a damage-response crew behind them. Tumours break the gates to grow and then depend on the ones they have left; the drugs here either hold a gate shut (CDK4/6 inhibitors) or force one open so the cell divides into death (WEE1, ATR, PARP, Aurora and MPS1 inhibitors). Pink means an approved drug exists.
Hover or focus a node for where it acts and its drugs; click for its row.
approved drug against it checkpoint member, no approval yet gate
The first gate. Cyclin D and CDK4/6 phosphorylate RB, which lets the cell commit to copying its DNA; p16 holds CDK4/6 back. Hormone-driven breast cancers lean on this gate, which is why CDK4/6 inhibitors work there.
Cyclin D-CDK4 complexes phosphorylate RB at the G1/S transition, releasing E2F; CDK6 is expressed ubiquitously and accumulates in squamous cell carcinomas and proliferating haematopoietic progenitors. UniProt Q00534
The regulatory component of the cyclin D1-CDK4 complex that phosphorylates RB at G1/S. UniProt P24385
A tumour suppressor and key regulator of the G1/S transition: the hypophosphorylated form binds E2F transcription factors and blocks their targets. UniProt P06400
Widely expressed, not detected in brain or skeletal muscle; binds CDK4 and CDK6 and stops them pairing with cyclin D and phosphorylating RB. UniProt P42771
The second gate, held shut by ATR, CHK1 and WEE1 until copied DNA is checked. Tumours that have lost p53 cannot stop at the first gate, so they rely on this one; drugs that force it open push them into a lethal mitosis.
“Tumour cells lacking functional p53 are defective in the G1/S checkpoint and become highly dependent on the G2/M checkpoint to maintain genomic stability, and are consequently vulnerable to WEE1 inhibitors, which override the G2/M checkpoint and induce cell death through mitotic catastrophe.” Chen et al. 2021, Front Med: WEE1 inhibitors and statins in cancers with p53 mutations
Ubiquitous, highest in testis; a sensor kinase that starts checkpoint signalling on replication stalling, ultraviolet light or ionising radiation. UniProt Q13535
Ubiquitous, most abundant in thymus, testis, small intestine and colon; required for checkpoint arrest and repair activation when DNA is damaged or unreplicated. UniProt O14757
A negative regulator of entry into mitosis that phosphorylates CDK1 on tyrosine 15, peaking in G2. UniProt P30291
Placenta and colon (UniProt tissue); acts throughout M phase on centrosome maturation, spindle assembly, cohesin removal and mitotic exit. UniProt P53350
The sensors and repair crews behind both gates. ATM and ATR detect breaks and stalled forks, CHK1 and CHK2 relay the alarm, p53 decides between pause, repair and death, and PARP patches single-strand breaks. Cancers that have lost one route depend on the others.
Pancreas, kidney, skeletal muscle, liver, lung, placenta, brain, heart, spleen, thymus, testis, ovary, small intestine, colon and leukocytes; the sensor kinase for double-strand breaks. UniProt Q13315
High in testis, spleen, colon and peripheral blood leukocytes; relays double-strand break signals into arrest, repair or apoptosis. UniProt O96017
Ubiquitous; a transcription factor that induces cell-cycle arrest, DNA repair or apoptosis, mutated in more than half of cancers. UniProt P04637
A poly-ADP-ribosyltransferase with a key role in DNA repair; its inhibitors are lethal to cells that have also lost homologous recombination. UniProt P09874
The last gate, inside mitosis. MPS1, BUB1 and Aurora B keep the cell from pulling its chromosomes apart until every one is attached; Aurora A and PLK1 build the spindle. Taxanes and vinca alkaloids kill by holding this gate shut for good.
“Vinca alkaloids and taxanes kill cancer cells through chronic arrest in mitosis as a consequence of chronic spindle assembly checkpoint activation.” Yuan et al. 2015: targeting the spindle assembly checkpoint for breast cancer treatment
High in testis, weak in skeletal muscle, thymus and spleen; high in colon, ovarian, prostate, neuroblastoma, breast and cervical cancer cell lines. Builds the spindle and separates centrosomes. UniProt O14965
High in thymus; spleen, lung, testis, colon, placenta and fetal liver; up-regulated in cancer cells during M phase, absent from normal liver and high in metastatic liver. UniProt Q96GD4
Present in rapidly proliferating cell lines; phosphorylates MAD1 to arm the spindle assembly checkpoint and repairs wrong kinetochore attachments. UniProt P33981
High in testis and thymus, less in colon, spleen, lung and small intestine; tissues with a high mitotic index. Assembles checkpoint proteins at the kinetochore. UniProt O43683
Sources. Identifiers from the HGNC REST API; where each protein acts from the UniProt function or tissue-specificity comment for the accession named; the p53-loss dependency and the taxane mechanism from the reviews quoted under their gates; drug statuses from the linked drug records; phases for agents without a record, and every stopped programme, from the ClinicalTrials.gov study cited. Taxonomy in src/data/checkpoint-map.ts.