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.

Prexasertib, a checkpoint kinase inhibitor: from preclinical data to clinical development / Angius, Gesuino; Tomao, Silverio; Stati, Valeria; Vici, Patrizia; Bianco, Vincenzo; Tomao, Federica. - In: CANCER CHEMOTHERAPY AND PHARMACOLOGY. - ISSN 0344-5704. - (2019), pp. 1-12. [10.1007/s00280-019-03950-y]

Prexasertib, a checkpoint kinase inhibitor: from preclinical data to clinical development

Tomao, Silverio
Secondo
;
Stati, Valeria;Tomao, Federica
Ultimo
2019

Abstract

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.
2019
Advanced squamous cell carcinoma (SCC); CHK inhibitors; CHK1; CHK2; Checkpoint kinase 1 and 2; LY2606368; Ovarian cancer; PARP inhibitors; Prexasertib
01 Pubblicazione su rivista::01g Articolo di rassegna (Review)
Prexasertib, a checkpoint kinase inhibitor: from preclinical data to clinical development / Angius, Gesuino; Tomao, Silverio; Stati, Valeria; Vici, Patrizia; Bianco, Vincenzo; Tomao, Federica. - In: CANCER CHEMOTHERAPY AND PHARMACOLOGY. - ISSN 0344-5704. - (2019), pp. 1-12. [10.1007/s00280-019-03950-y]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1349160
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