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

Angius, Gesuino; Tomao, Silverio; Stati, Valeria; Vici, Patrizia; Bianco, Vincenzo; Tomao, Federica

doi:10.1007/s00280-019-03950-y

Cited by 48 publications

(44 citation statements)

References 43 publications

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“…The ATR-Chk1 pathway is a key regulator of replication checkpoint and DNA damage repair [30]. In recent years efficacy of small molecule inhibitors of Chk1 has been tested in combination with DNA damaging agents in clinical trials against solid tumors, myeloid leukemia and small cell lung carcinoma with some favorable outcomes [31,32,33,34]. We were particularly interested to examine the effects of MK-8776 because of its higher selectivity against Chk1 over Chk2 [35].…”

Section: Resultsmentioning

confidence: 99%

Targeting DNA Damage Response as a Strategy to Treat HPV Infections

Banerjee

Moore

Parker

et al. 2019

IJMS

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Mucosotropic human papillomaviruses (HPVs) cause prevalent anogenital infections, some of which can progress to cancers. It is imperative to identify efficacious drug candidates, as there are few therapeutic options. We have recapitulated a robust productive program of HPV-18 in organotypic raft cultures of primary human keratinocytes. The HPV E7 protein induces S phase reentry, along with DNA damage response (DDR) in differentiated cells to support viral DNA amplification. A number of small molecule inhibitors of DDR regulators are in clinical use or clinical trials to treat cancers. Here, we used our raft culture system to examine effects of inhibitors of ATR/Chk1 and ATM/Chk2 on HPV infection. The inhibitors impaired S-phase reentry and progression as well as HPV DNA amplification. The Chk1 inhibitor MK-8776 was most effective, reducing viral DNA amplification by 90–99% and caused DNA damage and apoptosis, preferentially in HPV infected cells. We found that this sensitivity was imparted by the E7 protein and report that MK-8776 also caused extensive cell death of cervical cancer cell lines. Furthermore, it sensitized the cells to cisplatin, commonly used to treat advanced cervical cancer. Based on these observations, the Chk1 inhibitors could be potential effective agents to be re-purposed to treat the spectrum of HPV infections in single or combination therapy.

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Section: Resultsmentioning

confidence: 99%

Targeting DNA Damage Response as a Strategy to Treat HPV Infections

Banerjee

Moore

Parker

et al. 2019

IJMS

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“…To date, several selective inhibitors of ATR, M6620 (VX-970 or berzosertib), M4344 (VX-803), AZD6738 and BAY1895344, and CHK1, prexasertib (LY2606368), GDC-575 (ARRY-575; RG7741) and CCT245737 (SRA737), have been tested in clinical trials, but have not yet been approved [ 72 , 73 ]. For instance, prexasertib, which is a second-generation small-molecule inhibitor of CHK1, has been evaluated as both a single agent and in combination with other targeted agents or cytotoxic chemotherapies in adults and pediatric patients with tumors [ 74 ]. Previous studies have indicated that prexasertib is potently antiproliferative in neuroblastoma cell lines and xenograft mouse models [ 75 , 76 ].…”

Section: “Accelerating” the Cell Cycle To Induce Catastrophic Cell Deathmentioning

confidence: 99%

Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?

Ando

Nakagawara

2021

Biomolecules

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Unrestrained proliferation is a common feature of malignant neoplasms. Targeting the cell cycle is a therapeutic strategy to prevent unlimited cell division. Recently developed rationales for these selective inhibitors can be subdivided into two categories with antithetical functionality. One applies a “brake” to the cell cycle to halt cell proliferation, such as with inhibitors of cell cycle kinases. The other “accelerates” the cell cycle to initiate replication/mitotic catastrophe, such as with inhibitors of cell cycle checkpoint kinases. The fate of cell cycle progression or arrest is tightly regulated by the presence of tolerable or excessive DNA damage, respectively. This suggests that there is compatibility between inhibitors of DNA repair kinases, such as PARP inhibitors, and inhibitors of cell cycle checkpoint kinases. In the present review, we explore alterations to the cell cycle that are concomitant with altered DNA damage repair machinery in unfavorable neuroblastomas, with respect to their unique genomic and molecular features. We highlight the vulnerabilities of these alterations that are attributable to the features of each. Based on the assessment, we offer possible therapeutic approaches for personalized medicine, which are seemingly antithetical, but both are promising strategies for targeting the altered cell cycle in unfavorable neuroblastomas.

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“…102 Further evaluation of prexasertib is in progress in patients with advanced, BRCA-mutated ovarian cancer. 103 Acting in concert with CHKs (i.e. CHK1), the ataxia telangiectasia mutated and Rad3-related (ATR) serine threonine protein kinase contributes to genomic stability by regulating initiation of DNA replication and DNA repair.…”

Section: Protein Kinase-mediated Pathwaysmentioning

confidence: 99%

Ovarian cancer: new strategies and emerging targets for the treatment of patients with advanced disease

Arend

Jackson-Fisher

Jacobs

et al. 2021

Cancer Biology & Therapy

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Recently approved therapies have contributed to a significant progress in the management of ovarian cancer; yet, more options are needed to further improve outcomes in patients with advanced disease. Here we review the rationale and ongoing clinical trials of novel combination strategies involving chemotherapy, poly ADP ribose polymerase, programmed death 1 (PD-1)/PD-ligand 1 immune checkpoint and/or vascular endothelial growth factor receptor inhibitors. Further, we discuss novel agents aimed at targets associated with ovarian cancer growth or progression that are emerging as potential new treatment approaches. Among them, agents targeted to folate receptor α, tissue factor, and protein kinase-mediated pathways (WEE1 kinase, phosphatidylinositol-3 kinase α, cell cycle checkpoint kinase 1/2, ATR kinase) are currently in clinical development as mono- or combination therapies. If successful, findings from these extensive development efforts may further transform treatment of patients with advanced ovarian cancer.

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

Cited by 48 publications

References 43 publications

Targeting DNA Damage Response as a Strategy to Treat HPV Infections

Targeting DNA Damage Response as a Strategy to Treat HPV Infections

Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?

Ovarian cancer: new strategies and emerging targets for the treatment of patients with advanced disease

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