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Updated: Jan 19, 2026
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Prexasertib, a checkpoint kinase inhibitor: from preclinical data to clinical development
Gesuino Angius1, Silverio Tomao2, Valeria Stati3
1Medical Oncology, "Sapienza" University of Rome, Piazzale Aldo Moro, 5, 00185, Rome, RM, Italy. gesuino.angius@uniroma1.it.
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.
Insights
Checkpoint kinases 1 and 2 (CHK1/CHK2) regulate DNA replication and damage response. Prexasertib, a CHK1/CHK2 inhibitor, shows promise in preclinical studies for solid tumors, warranting further clinical evaluation.
Area of Science:
- Molecular Biology
- Cell Cycle Regulation
- DNA Damage Response
Background:
- Checkpoint kinases 1 and 2 (CHK1 and CHK2) are key regulators of DNA replication and cellular response to DNA damage.
- These kinases halt the cell cycle to allow DNA repair or initiate apoptosis if damage is irreparable.
- CHK1/CHK2 also play roles in initiating DNA replication, stabilizing replication forks, resolving replication stress, and coordinating mitosis.
Purpose of the Study:
- To evaluate prexasertib (LY2606368), a selective CHK1 and CHK2 inhibitor, for its potential in cancer therapy.
- To summarize preclinical findings on prexasertib's efficacy as monotherapy and in combination treatments.
- To highlight the need for further clinical trials to assess safety and efficacy of prexasertib combinations.
Main Methods:
- Preclinical studies investigating prexasertib's effects on cancer cells.
- Review of early clinical data for prexasertib in solid tumors.
- Analysis of combination therapies involving prexasertib with antimetabolites, PARP inhibitors, and platinum-based chemotherapy.
Main Results:
- Prexasertib monotherapy demonstrated induction of DNA damage and apoptosis in tumor cells in preclinical settings.
- Preclinical and early clinical data suggest potential for prexasertib in solid tumors.
- Combination therapies with prexasertib are being explored in ongoing clinical trials.
Conclusions:
- Prexasertib is a selective inhibitor of CHK1 and CHK2 with demonstrated preclinical anti-tumor activity.
- The drug shows potential for use in solid tumors, both as a single agent and in combination with other chemotherapeutics.
- Further clinical investigation is required to fully establish the safety and efficacy profile of prexasertib combination therapies.
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