Table 2.
Small molecule inhibitors targeting centrosome associated G2/M checkpoint regulators
| Specific targets | Functions | Clinical development | Combination with DNA-damaging agents | |
| Flavopiridol[128] | Cdk1, p21, Survivin | Bind to Cdc2, inhibit apoptosis | Phase I/II | paclitaxel, irinotecan, gemcitabine, IR |
| UCN-01[153-155] | Cdk1, Chk1/2 | Inhibit Chk1 and PKC activity, promote apoptosis | Phase I/II | fluorouracil, topotecan, cisplatin, IR, temozolomide |
| Daidzein[139] | Cdk1, p21Cip1, p57Kip2 | Inhibit Cdk1 and cell proliferation | Preclinical | NA |
| Caffeine [123-125] | ATM/ATR, PI3K | Inhibit ATM/ATR, cause G2 checkpoint abrogation, induce apoptosis | Phase I | Taxol, cisplatin |
| KU-55933[122,126] | ATM | Inhibit ATM | Phase I | NA |
| Berberine[140,141] | Wee1, 14-3-3, Cdk2, cyclinB, Cdc25c | Induce G2/M phase arrest and apoptosis | Preclinical | NA |
| 17AAG [145-147] | Chk1, Hsp90 | Downregulate Chk1, inhibit colony formation, induce apoptosis, abrogate G2/M checkpoint | Phase I/II | gemcitabine, cisplatin, topoisomerase I poisons, taxol, IR |
| XL844[148] | Chk1/2 | Enhance gemcitabine antitumor activity | Phase I | Gemcitabine |
| CHIR-124[149] | Chk1 | abrogate G2/M checkpoint, induce apoptosis | Preclinical | Topoisomerase I poisons |
| PF-00477736[150] | Chk1, cyclin B, Securin, Aurora | Inhibit Chk1, abrogates cell cycle arrest | Preclinical | Gemcitabine, carboplatin |
| PD0166285[127] | Wee1, Aurora A | Inhibit Wee1, abrogate G2/M checkpoint | Preclinical | NA |
| CEP-3891[143,151] | Chk1 | Abrogate G2/M checkpoint | Preclinical | IR |
| N-aryl-N'-pyrazinylurea [142,152] | Chk1 | Inhibit Chk1, inhibit cell proliferation | Preclinical | Doxorubicin, camptothecin |
| VX-680[166,170] | Aurora A, B | Block cell proliferation, disrupt bipolar spindle formation, accumulate of cell with 4N or greater DNA | Phase II | Vorinostat, docetaxel |
| Hesperadin[171] | Aurora kinase | Inhibit Aurora kinase activity | Phase I/II | NA |
| ZM447439[173] | Aurora A, B | Inhibit Aurora A, induce apoptosis | Phase I | NA |
| PHA-739358[164] | Aurora A, B, C | Inhibit proliferation | Phase I | NA |
| PHA-680632 [167,163] | Aurora A | Inhibit Aurora A and proliferation | Phase I | IR |
| ON01910[179] | Plk1, Cdk1 | Inhibit Plk1, induce mitosis arrest | Preclinical | NA |
Abbreviation: NA, not available; IR, ionizing radiation