TY - JOUR
T1 - Prexasertib, a checkpoint kinase inhibitor
T2 - from preclinical data to clinical development
AU - Angius, Gesuino
AU - Tomao, Silverio
AU - Stati, Valeria
AU - Vici, Patrizia
AU - Bianco, Vincenzo
AU - Tomao, Federica
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Checkpoint kinases 1 and 2 (CHK1 and CHK2) are important multifunctional proteins of the kinase family. Their main function is to regulate DNA replication and DNA damage response. If a cell is exposed to exogenous damage to its DNA, CHK1/CHK2 stops the cell cycle to give time to the cellular mechanisms to repair DNA breakage and apoptosis too, if the damage is not repairable to activate programmed cell death. CHK1/CHK2 plays a crucial role in the repair of recombination-mediated double-stranded DNA breaks. The other important functions performed by these proteins are the beginning of DNA replication, the stabilization of replication forks, the resolution of replication stress and the coordination of mitosis, even in the absence of exogenous DNA damage. Prexasertib (LY2606368) is a small ATP-competitive selective inhibitor of CHK1 and CHK2. In preclinical studies, prexasertib in monotherapy has shown to induce DNA damage and tumor cells apoptosis. The preclinical data and early clinical studies advocate the use of prexasertib in solid tumors both in monotherapy and in combination with other drugs (antimetabolites, PARP inhibitors and platinum-based chemotherapy). The safety and the efficacy of combination therapies with prexasertib need to be better evaluated in ongoing clinical trials. CHK-1 and CHK2 have an important role in DNA damage response.Inhibition of CHK1 may be an attractive therapeutic strategy to improve outcomes for patients with solid tumorsPrexasertib is a CHK-1/2 inhibitor.Prexasertib demonstrated efficacy in early clinical trials when combined with other drugs.There is a potential role in combining prexasertib with chemotherapy and immunotherapy.The safety of combination therapy needs to be better investigated.
AB - Checkpoint kinases 1 and 2 (CHK1 and CHK2) are important multifunctional proteins of the kinase family. Their main function is to regulate DNA replication and DNA damage response. If a cell is exposed to exogenous damage to its DNA, CHK1/CHK2 stops the cell cycle to give time to the cellular mechanisms to repair DNA breakage and apoptosis too, if the damage is not repairable to activate programmed cell death. CHK1/CHK2 plays a crucial role in the repair of recombination-mediated double-stranded DNA breaks. The other important functions performed by these proteins are the beginning of DNA replication, the stabilization of replication forks, the resolution of replication stress and the coordination of mitosis, even in the absence of exogenous DNA damage. Prexasertib (LY2606368) is a small ATP-competitive selective inhibitor of CHK1 and CHK2. In preclinical studies, prexasertib in monotherapy has shown to induce DNA damage and tumor cells apoptosis. The preclinical data and early clinical studies advocate the use of prexasertib in solid tumors both in monotherapy and in combination with other drugs (antimetabolites, PARP inhibitors and platinum-based chemotherapy). The safety and the efficacy of combination therapies with prexasertib need to be better evaluated in ongoing clinical trials. CHK-1 and CHK2 have an important role in DNA damage response.Inhibition of CHK1 may be an attractive therapeutic strategy to improve outcomes for patients with solid tumorsPrexasertib is a CHK-1/2 inhibitor.Prexasertib demonstrated efficacy in early clinical trials when combined with other drugs.There is a potential role in combining prexasertib with chemotherapy and immunotherapy.The safety of combination therapy needs to be better investigated.
KW - Advanced squamous cell carcinoma (SCC)
KW - Checkpoint kinase 1 and 2
KW - CHK inhibitors
KW - CHK1
KW - CHK2
KW - LY2606368
KW - Ovarian cancer
KW - PARP inhibitors
KW - Prexasertib
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U2 - 10.1007/s00280-019-03950-y
DO - 10.1007/s00280-019-03950-y
M3 - Review article
C2 - 31512029
AN - SCOPUS:85073940730
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
SN - 0344-5704
ER -