Table 1.
Inhibitors targeting proteins involved in centrosome duplication.
| Inhibitors Targeting | Enzymes | Pathways | Protein Target | Inhibitor | Mechanism of Action of Inhibitors | Clinical Trial |
|---|---|---|---|---|---|---|
| Centriole disengagement | Rad21 | Centrosome duplication | Separase | Sepin-1 | Inhibits Rad21 cleavage by activated separase [16,17]. | Pre-clinical development [17]. |
| Centriole disengagement and centrosome maturation | Plk1 | Centrosome duplication | Plk1 | BI 2536 | 2-aminopyrimidine-containing ATP-competitive kinase inhibitor. Causes disruption of the spindle assembly leading to mitotic arrest and apoptosis [18]. | Phase II clinical trials completed in patients with prostatic and pancreatic neoplasms, breast cancer, endometrial cancer, head and neck cancer, non-small cell lung cancer and SCLC. https://clinicaltrials.gov/ct2/results?cond=Cancer&term=BI2536&cntry=&state=&city=&dist= |
| Volasertib (BI 6727) | Blocks cell division by competitively binding to the ATP-binding pocket of Plk1 [18,19]. | Phase II clinical trial completed in patients with ovarian cancer and urothelial cancer. https://clinicaltrials.gov/ct2/results?cond=Cancer&term=BI+6727&cntry=&state=&city=&dist= Phase III clinical trial in combination with low dose cytarabine in AML patients: NCT01721876. |
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| GSK461364 | ATP-competitive Plk1 inhibitor caused mitotic arrest through G2/M arrest [18]. | Phase I clinical trial completed in non-Hodgkins lymphoma: NCT00536835. | ||||
| ZK-thiazolidinone (TAL) |
ATP-competitive inhibitor specifically inhibits Plk1 and causes prometaphase-like mitotic arrest [18]. | Pre-clinical development [20]. | ||||
| Centriole disengagement and centrosome duplication | CDK2 | Cell cycle (G1/S transition) |
CDK2 | Milciclib (PHA-848125 AC) | ATP-competitive inhibitor of cyclin-dependent kinases (Cdks) that potently inhibits Cdk2/cyclin A (IC50 = 45 nM) [21]. | Phase I clinical trial completed in patients with advanced/metastatic solid tumours: NCT01300468. Phase II clinical trial in patients with malignant thymoma, thymic carcinoma and hepatocellular carcinoma. https://clinicaltrials.gov/ct2/results?cond=Cancer&term=PHA-848125+AC&cntry=&state=&city=&dist= |
| SU9516 | Inhibits pRb phosphorylation causing enhanced pRB/E2F complex formation and induces G1 and G2-M cell cycle arrest [22]. | Pre-clinical development. | ||||
| CDK2 and CDK1 | Butyrolactone I | An ATP-competitive inhibitor of CDKs which inhibits phosphorylation of pRB and transcription factor EF-1 and prevents cell cycle progression both at G1/S and G2/M transitions [23,24]. | Pre-clinical development. | |||
| RNA polymerase II | Cell cycle progression | Pan Cdk | Flavopiridol (Alvocidib or HMR 1275) | Causes downregulation of cyclin D1, c-MYC, and MCL-1 and induces apoptosis in tumour cells [25]. | Phase II clinical trial completed in prostate cancer, kidney cancer and endometrial cancer and phase II drug combination studies completed in esophageal cancer, liver cancer pancreatic cancer, breast cancer, head and neck cancer, germ cell tumours and ovarian epithelial cancer. https://clinicaltrials.gov/ct2/results?term=Flavopiridol&cond=cancer&age_v=&gndr=&type=&rslt=&phase=1&phase=2&phase=3&Search=Apply |
|
| pRb phosphorylation | R-547 (RG547) | ATP-competitive CDK inhibitor, inhibits retinoblastoma protein phosphorylation in tumour cells and induces apoptosis [25,26]. | Phase I clinical trial completed in patients with advanced solid tumours: NCT00400296. | |||
| Mcl-1 transcription | CYC-202 (R-roscovitine/Seliciclib) | Competes with ATP for its binding site on CDKs, reduces retinoblastoma protein phosphorylation and arrests cell cycle at G1, S, and G2-M phases [23,25,27,28]. | Phase I clinical trial of CYC-202 in sequential or concomitant combination therapies in patients with breast cancer (NCT01333423), non-small cell lung cancer (NCT00372073) and advanced solid tumours (NCT00999401). | |||
| polymerase (RNA Pol) II | SNS-032 | Reversibly inhibits phosphorylation of RNA polymerase II and causes RNA synthesis inhibition [29]. | Phase I clinical trial completed in patients with selected advanced solid tumours (NCT00292864) and advanced B-lymphoid malignancies (NCT00446342). | |||
| Centriole elongation and centrosome duplication | Plk4 | Centrosome duplication | Plk4 | CFI- 400945 | ATP competitive inhibitor and inhibits autophosphorylation of PLK4 at serine 305 [30]. | Phase I clinical trial in patients with advanced cancer (NCT01954316), and in relapsed or refractory AML or myelodysplastic syndrome (NCT03187288). |
| Centrosome maturation and separation | Aurora-A | Cell cycle (mitotic regulator) and centrosome maturation |
Aurora-A | Alisertib (MLN8237) | Binds and inhibits Aurora-A, causing delayed mitotic entry and cell cycle arrest, leading to the formation of cells with tetraploid DNA content [31]. | Phase II clinical trial completed in prostate cancer, childhood solid tumours or leukaemia (NCT01799278), and adult advanced non-haematological malignancies (NCT01045421). Phase II combination studies with Paclitaxel in small cell lung cancer, breast cancer and combination therapy in malignant rhabdoid tumours. https://clinicaltrials.gov/ct2/results?term=MLN8237&cond=cancer+and+neoplasia&age_v=&gndr=&type=&rslt=&phase=1&phase=2&phase=3&Search=Apply Phase III clinical trial evaluating Alisertib, compared with Pralatrexate or Gemcitabine or Romidepsin, in patients with relapsed or refractory peripheral T-Cell Lymphoma: NCT01482962. |
| ENMD-2076 | Causes G2-M arrest and a decrease in the intercentrosomal distance, with induction of monopolar spindles and apoptosis [32]. | Phase II clinical trial completed in patients with ovarian cancer, ovarian clear cell carcinomas, haematological malignancies, hepatocellular, sarcoma and triple negative breast cancer. https://clinicaltrials.gov/ct2/results?cond=Cancer&term=ENMD-2076&cntry=&state=&city=&dist= |
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| MK-5108 (VX-689) | Inhibits Aurora-A kinase by competitively binding to the ATP binding site [33]. | Phase I clinical trial completed in patients with advanced solid tumours: NCT00543387. | ||||
| KW-2449 | A multikinase inhibitor which causes downregulation of Aurora kinases and leads to G2/M arrest [34]. | Phase I clinical trial in patients with acute myelogenous leukaemia (AML) myelodysplastic syndromes and chronic myelogenous leukaemia (NCT00779480, NCT00346632). | ||||
| XL228 | Multi-tyrosine kinases inhibitor which inhibits Aurora-A, the T315I mutant form of the Abl protein, IGF1R, Src tyrosine kinase. It prevents tumor angiogenesis, cell proliferation, and metastasis [35]. | Phase I clinical trial in patients with advanced malignancies (NCT00526838), and chronic myeloid leukaemia or philadelphia-chromosome-positive acute lymphocytic leukaemia (NCT00464113). | ||||
| MLN8054 | An ATP-competitive inhibitor which targets Aurora-A and causes monopolar, acentriolar bipolar, and multipolar spindles, leading to chromosomal segregation defects, aneuploidy and cell death [36]. | Phase I clinical trials in patients with advanced malignancies (NCT00652158) and breast, colon, pancreatic and bladder tumours (NCT00249301). | ||||
| Aurora-B | Cell cycle (sister chromatid cohesion) |
Aurora-B | Barasertib (AZD1152-HQPA) | Competitively blocks the ATP-binding pocket of Aurora-B kinase [31,33,37]. | Phase I clinical trial completed in patients with AML (NCT01019161, NCT00926731). Phase I/II clinical trial in in patients with relapsed acute myeloid leukaemia/high-risk myelodysplastic syndrome (NCT03217838). |
|
| BI811283 | Inhibits by binding to the ATP binding pocket of Aurora-B [33]. | Phase I clinical trial completed in patients with various solid tumours: NCT00701324. Phase I/IIa combination study with Cytarabine completed in patients with previously untreated acute myeloid leukaemia: NCT00701324. |
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| Aurora-A/B/C | Cell cycle | (Pan Aurora) Aurora-A/B/C |
Danusertib (PHA-739358) | ATP competitive pan-Aurora kinase inhibitor that inhibits the catalytic domain of Aurora kinases [31,33]. | Phase II study completed in patients with metastatic hormone refractory prostate cancer (NCT00766324), multiple myeloma (NCT00872300) and leukaemia (NCT00335868). | |
| Aurora-A/B | Aurora-A/B | PF-03814735 | ATP competitive reversible inhibitor which blocks cytokinesis, resulting in decreased cell proliferation and the appearance of polyploid multinucleate cells [31,33,38]. | Phase I clinical trial completed in patients with advanced solid tumours: NCT00424632. | ||
| Aurora-A/B/C | Aurora-A/B/C | AMG 900 | ATP-competitive inhibitor of Aurora kinases, causing inhibition of autophosphorylation of Aurora-A and -B [31,33]. | Phase I clinical trial completed in active study in advanced malignancy and solid tumours (NCT00858377) and acute myeloid leukaemia (NCT01380756). | ||
| Linker dissociation | NIMA Related Kinase 2 (Nek2) | Centrosome duplication | Nek2 | JH295 | Irreversibly inhibits Nek2 via alkylation of residue Cys22 without affecting the mitotic kinases, Cdk1, Aurora-B, or Plk1 [39]. | Pre-clinical development. |
| NCL 00017509 | Binds to ATP domain of Nek2 and causes irreversible inhibition [40]. | Pre-clinical development. | ||||
| Centrosome separation and spindle fibre formation | Cdk1 | Cell cycle (G2/M transition) |
CDK1/cyclin B1 | RO-3306 | Binds to ATP binding pocket and inhibits CDK1/cyclin B1 [41,42]. | Pre-clinical development. |
| CDK1 | CGP 74514A | Binds to ATP binding pocket and reduces Akt phosphorylation, increasing mitochondrial damage and inducing apoptosis [43,44]. | Pre-clinical development. | |||
| KSP/Eg5 | (Cell cycle) mitotic spindle pole separation |
KSP/Eg5 | Monastrol | ATP non-competitive reversible inhibitor which binds to the Eg5-ADP complex and prevents force generation and kinesin motility [45]. | Pre-clinical development. | |
| Ispinesib (SB-715992) | ATP non-competitive reversible inhibitor which binds to the Eg5-ADP complex and prevents force generation and kinesin motility [46,47]. | Phase II clinical trial completed in patients with breast cancer, prostate cancer, ovarian cancer, non-small cell lung cancer, liver cancer, kidney cancer, colorectal cancer and melanoma. https://clinicaltrials.gov/ct2/results?cond=cancer&term=Ispinesib+SB-715992&cntry=&state=&city=&dist= |
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| MK-0731 | ATP non-competitive reversible inhibitor which binds to the Eg5-ADP complex and prevents force generation and kinesin motility [45]. | Phase I clinical trial completed in patients with advanced solid tumours: NCT00104364. | ||||
| KSP/Eg5 mcl-1 |
KSP/Eg5 mcl-1 |
Filanesib (ARRY-520) | Non-ATP competitive inhibitor which binds to Eg5 at the same site as monastrol and induces cell cycle arrest at mitosis, leading to apoptosis [45,48]. | Phase I/II clinical trial completed in patients with advanced solid tumours and haematological malignancies. https://clinicaltrials.gov/ct2/results?cond=cancer&term=ARRY-520&cntry=&state=&city=&dist= |