Cell-cycle and DNA-damage checkpoints
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.
The cell-cycle ring
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
G1/S gate
CDK4/6, Cyclin D1, RB, p16 (CDKN2A), p53G2/M gate
ATR, CHK1, WEE1, PLK1DNA-damage response
ATR, CHK1, ATM, CHK2, p53, PARP1Spindle assembly checkpoint
PLK1, Aurora A, Aurora B, MPS1 (TTK), BUB1G1/S: the decision to copy DNA
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.
- MemberWorks withWhere it acts
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
Approvals by cancerHER2-positive breast cancerHigh-risk early HR-positive breast cancerHR-positive / HER2-negative breast cancerHR-positive metastatic breast cancer after CDK4/6 inhibitorsSmall-cell lung cancer9 approvals by region
- US 2015, Palbociclib: HR+/HER2- advanced breast cancer with endocrine therapy
- US 2017, Ribociclib: HR+/HER2- advanced breast cancer
- US 2017, Abemaciclib: HR+/HER2- advanced breast cancer
- China 2021, Dalpiciclib: HR-positive, HER2-negative advanced breast cancer with fulvestrant after endocrine therapy (DAWNA-1)
- US 2021, Abemaciclib: Adjuvant high-risk node-positive HR+/HER2- early breast cancer
- US 2021, Trilaciclib: To decrease chemotherapy-induced myelosuppression in adults receiving platinum-etoposide or topotecan for extensive-stage small cell lung cancer
- China 2023, Dalpiciclib: First-line HR-positive, HER2-negative advanced breast cancer with an aromatase inhibitor (DAWNA-2)
- US 2024, Ribociclib: Adjuvant stage II-III HR+/HER2- breast cancer at high risk of recurrence
- US 2026, Palbociclib: HR+/HER2+ advanced breast cancer maintenance with anti-HER2 and endocrine therapy
- Works withWhere it acts
The regulatory component of the cyclin D1-CDK4 complex that phosphorylates RB at G1/S. UniProt P24385
Best drug statusNo product with a statusApprovals by cancerNoneDrugsNo product in the corpus - Works withWhere it acts
A tumour suppressor and key regulator of the G1/S transition: the hypophosphorylated form binds E2F transcription factors and blocks their targets. UniProt P06400
Best drug statusNo product with a statusApprovals by cancerNoneDrugsNo product in the corpus - MemberWorks withWhere it acts
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
Best drug statusNo product with a statusApprovals by cancerNoneDrugsNo product in the corpus
G2/M: the decision to divide
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
- Works withWhere it acts
Ubiquitous, highest in testis; a sensor kinase that starts checkpoint signalling on replication stalling, ultraviolet light or ionising radiation. UniProt Q13535
Best drug statusPhase 3CeralasertibSmall molecule1 stopped
- Ceralasertib (AZD6738) programme: The study terminated because the clinical development programme for ceralasertib has been discontinued (registry text, December 2025). ClinicalTrials.gov NCT06929260
Approvals by cancerNone - Where it acts
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
Best drug statusNo product with a status1 stopped
- Prexasertib (Lilly era): Eli Lilly prematurely terminated the study. ClinicalTrials.gov NCT02203513
Approvals by cancerNoneDrugsNo product in the corpus- Prexasertib (ACR-368, a CHK1/2 inhibitor) completed phase 2 in platinum-resistant ovarian cancer and is in phase 2 in endometrial cancer. ClinicalTrials.gov NCT03414047
- MemberWorks withWhere it acts
A negative regulator of entry into mitosis that phosphorylates CDK1 on tyrosine 15, peaking in G2. UniProt P30291
Best drug statusPhase 3AzenosertibSmall molecule2 stopped
- Adavosertib (AZD1775) programme: Study terminated because the clinical development programme for adavosertib has been discontinued. ClinicalTrials.gov NCT04949425
- Azenosertib with carboplatin and pembrolizumab in triple-negative breast cancer: Terminated due to concern for toxicity from previously reported serious adverse events; never reached phase 2. ClinicalTrials.gov NCT06351332
Approvals by cancerNone - Works withWhere it acts
Placenta and colon (UniProt tissue); acts throughout M phase on centrosome maturation, spindle assembly, cohesin removal and mitotic exit. UniProt P53350
Best drug statusPhase 2OnvansertibSmall molecule1 stopped
- Volasertib (Boehringer Ingelheim): Development programme of study drug volasertib was stopped by Boehringer Ingelheim due to manufacturing problems. ClinicalTrials.gov NCT02198482
Approvals by cancerNoneDrugs
DNA-damage response
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.
- Works withWhere it acts
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
Best drug statusNo product with a statusApprovals by cancerNoneDrugsNo product in the corpus- AZD1390 (brain-penetrant ATM inhibitor) is an arm of a phase 2/3 glioblastoma platform study with radiotherapy. ClinicalTrials.gov NCT03970447
- AZD0156 (ATM inhibitor) completed a phase 1 study alone and with olaparib or chemotherapy. ClinicalTrials.gov NCT02588105
- MemberWhere it acts
High in testis, spleen, colon and peripheral blood leukocytes; relays double-strand break signals into arrest, repair or apoptosis. UniProt O96017
Best drug statusNo product with a statusApprovals by cancerNoneDrugsNo product in the corpus- No CHK2-selective agent is in trials under the names the corpus knows; prexasertib inhibits CHK1 and CHK2 together. ClinicalTrials.gov NCT03414047
- MemberWorks withWhere it acts
Ubiquitous; a transcription factor that induces cell-cycle arrest, DNA repair or apoptosis, mutated in more than half of cancers. UniProt P04637
Approvals by cancerNoneDrugs- Rezatapopt (PC14586), a corrector of the TP53 Y220C mutant, is in phase 1/2. ClinicalTrials.gov NCT04585750
- Works withSynthetic lethality with BRCA1/2 and other homologous-rec…Where it acts
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
Approvals by cancerBRCA or PALB2-mutant pancreatic ductal adenocarcinomaEarly triple-negative breast cancerHigh-grade serous ovarian cancerHR-positive / HER2-negative breast cancerMetastatic castration-resistant prostate cancerMetastatic triple-negative breast cancerand 5 more →10 approvals by region
- US 2014, Olaparib: gBRCA ovarian cancer ≥3 lines
- US 2016, Rucaparib: BRCA-mutated advanced ovarian cancer after ≥2 chemotherapies (later narrowed)
- US 2017, Niraparib: Recurrent ovarian cancer maintenance
- US 2018, Olaparib: gBRCA HER2- metastatic breast cancer
- US 2018, Rucaparib: Maintenance in recurrent ovarian cancer after platinum response (now BRCA-mutated only)
- US 2018, Talazoparib: gBRCA HER2- locally advanced/metastatic breast cancer
- US 2020, Niraparib: First-line ovarian maintenance
- US 2020, Rucaparib: BRCA-mutated mCRPC after ARPI and taxane
- US 2022, Olaparib: Adjuvant gBRCA high-risk HER2- early breast cancer
- US 2023, Talazoparib: HRR-mutant mCRPC with enzalutamide
Spindle assembly checkpoint
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
- MemberWorks withWhere it acts
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
Approvals by cancerNoneDrugs- Alisertib completed a phase 3 trial against investigator's choice in relapsed peripheral T-cell lymphoma. ClinicalTrials.gov NCT01482962
- MemberWorks withWhere it acts
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
Best drug statusNo product with a status1 stopped
- Barasertib (AZD2811 nanoparticle): Strategic decision (phase 1 study terminated). ClinicalTrials.gov NCT03217838
Approvals by cancerNoneDrugsNo product in the corpus - MemberWhere it acts
Present in rapidly proliferating cell lines; phosphorylates MAD1 to arm the spindle assembly checkpoint and repairs wrong kinetochore attachments. UniProt P33981
Best drug statusNo product with a statusApprovals by cancerNoneDrugsNo product in the corpus- CFI-402257 (TTK inhibitor) is in phase 1/2 alone, with fulvestrant, and with paclitaxel in breast cancer. ClinicalTrials.gov NCT05251714
- Works withWhere it acts
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
Best drug statusNo product with a statusApprovals by cancerNoneDrugsNo product in the corpus- No BUB1 inhibitor was found in ClinicalTrials.gov (a search for BAY 1816032 returned no studies); the target is preclinical. ClinicalTrials.gov search, 24 September 2026
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.